Metab Brain Dis
DOI 10.1007/s11011-017-9995-2

ORIGINAL ARTICLE

Novel phenotypes of pyridox(am)ine-5’-phosphate oxidase
deficiency and high prevalence of c.445_448del mutation
in Chinese patients
Jiao Xue 1 & Xingzhi Chang 1 & Yuehua Zhang 1 & Zhixian Yang 1

Received: 24 December 2016 / Accepted: 13 March 2017
# Springer Science+Business Media New York 2017

Abstract To analyze the clinical and genetic characteristics
of Chinese patients with pyridox(am)ine-5′-phosphate oxidase
(PNPO) deficiency. The clinical presentations and the responses to treatments were analyzed in 4 patients. Blood and
urinary metabolic screenings, electroencephalogram (EEG),
brain magnetic resonance imaging (MRI) and epilepsyrelated genes detection were performed in all patients.
Patient 1 and 2 were identical twin brothers, who were born
at 35+5 w gestation with a sign of encephalopathy. Their seizures started within the first day and could not be controlled
by pyridoxine or pyridoxal-5′-phosphate (PLP) completely.
Patient 3 presented seizures at 5 months, responding well to
pyridoxine. Seizures in patient 4 began at 40 days after birth
and were controlled by valproic acid and topiramate. EEG
showed atypical hypsarrhythmia or multifocal epileptiform
discharges in 3 patients, and showed normality in patient 4.
MRI showed nonspecific abnormality or normality. Blood
metabolic screening showed multiple amino acids level abnormalities in all cases. Urinary metabolic screening showed
Electronic supplementary material The online version of this article
(doi:10.1007/s11011-017-9995-2) contains supplementary material,
which is available to authorized users.
* Yuehua Zhang
zhangyhdr@126.com
* Zhixian Yang
zhixian.yang@163.com
Jiao Xue
xuejiao2277@163.com
Xingzhi Chang
changxingzhi7318@163.com
1

Department of Pediatrics, Peking University First Hospital, No.1,
Xi’anmen Street, Xicheng District, Beijing 100034, China

vanillactic acid prominently elevated in 3 patients. Genetic
analysis revealed 5 mutations of PNPO, three of which were
novel. The mutation c.445_448del was carried by the twins
and patient 3. Assessment of psychomotor development indicated severe delay in 3 patients and borderline to mild delay in
patient 3. This is the first time to report patients with PNPO
deficiency diagnosed by gene analysis in China. The novel
clinical characteristics and novel mutations found here expanded the phenotypes and genotypes of this disease.
Further, the frameshift mutation c.445_448del might be high
prevalence in PNPO deficiency in Chinese patients.
Keywords Pyridoxal-5′-phosphate . Pyridoxine . PNPO
gene . High prevalence mutation

Introduction
In 2002, Kuo and Wang (2002) first described a neonate
whose seizures were controlled by pyridoxal-5′-phosphate
(PLP) but resistant to pyridoxine. Then, this phenomenon
was recognized as an epileptic disorder in which neonatal
seizures did not respond to antiepileptic drugs (AEDs) and
pyridoxine, but respond to PLP. The underlying genetic defect
in the PNPO gene was identified in 2005 (Mills et al. 2005),
identifying its autosomal recessive inheritance (OMIM
610090). In the past, it was named as PLP-dependent epilepsy
or PLP-responsive epilepsy (Veerapandiyan et al. 2011;
Veeravigrom et al. 2015). As a further study found that seizures could be completely or partially responsive to pyridoxine in some patients (Mills et al. 2014), the above two names
became no longer appropriate. Then the name of pyridox(am)ine-5′-phosphate oxidase (PNPO) deficiency was used
widely. PNPO is the rate-limiting enzyme in the synthesis of
PLP from pyridoxine or pyridoxamine. PLP is the only active

+: complete response; ±: partial response; null: not use

# Patient 1 and patient 2 are identical twin brothers. * Patients 1 and 2 showed initial worsening of seizures with PLP

MD Multifocal discharges; Hyps Hypsarrhythmia; PWMA Periventricular white matter attenuation; BVW Bilateral ventricles widened

40 d
at term Normal
M
4

MS Myoclonic seizures; IS Infantile spasms; FS Focal seizures; GTCS Generalized tonic-clonic seizures

Yes/No

?/null

Normal

Normal

c.148G > A;c.347G > A

Severe delay
Borderline to
mild delay
Severe delay
PWMA,BVW c.445_448del;c.481C > T
Normal
c.445_448del;c.413G > A
MD
MD
±/±*
+/null

MD, Hyps PWMA,BVW c.445_448del;c.481C > T
±/±*
Yes/Yes

Yes/Yes
Yes/No
35+5 w Encephao -pathy <24 h
at term Normal
5m

Seizure onset Seizure type
Birth history

MS?IS,FS,GTCS PB,VPA,CZP,
TPM,LEV
MS?IS,FS,GTCS PB,VPA,CZP, TPM,LEV
GTCS
VPA,OXC,LEV,
CZP,PB
FS
VPA,TPM
M
M

Patient 1 and 2 were identical twin brothers. They were born at
35+5 weeks gestation to healthy non-consanguineous parents
by caesarean section, with a birth weight of 1895 g and 1745 g

2#
3

Patient 1 and 2

patient Sex GA

Clinical presentation (Table 1)

Summary of clinical and molecular findings in our patients

Results

Table 1

Biochemical studies, blood and urinary metabolic screenings,
electroencephalography (EEG) and magnetic resonance imaging (MRI) were performed in all patients. Of them, the metabolic screenings were done in patient 1, 2 and 4 when they
were on pyridoxine and in patient 3 before using pyridoxine.
The psychomotor development was assessed according to
clinical judgment and/or Gesell developmental scale.
Genetic analysis was performed through targeted nextgeneration sequencing, within a custom-designed panel capturing the coding exons of 470 genes associated with epilepsy,
including PNPO, ALDH7A1 and so on (Xue et al. 2016). The
pathogenicity of the identified missense substitutions was predicted based on the lack of such mutations in the control
samples and on the conservation of substituted nucleotides
and amino acids. We also predicted the functional alteration
of the novel missense mutations using polymorphism
phenotyping-2 (PolyPhen-2) and MutationTaster.

AEDs

Methods

Received Response

Pyridoxine/PLP

EEG

This study was approved by the Ethical Committee of Peking
University First Hospital. The individuals’ parents in this
manuscript have given written informed consent to publish
the case details. All data were analyzed anonymously.

35+5 w Encephao -pathy <24 h

Ethics statement

M

MRI

Materials and methods

1#

form of vitamin B6, and it is involved in a wide range of
biochemical reactions, including the metabolism of amino
acids and glycogen, the synthesis of nucleic acids, hemoglobin, sphingomyelin and neurotransmitters (Khayat et al.
2008). So in addition to epilepsy, other presentations including hepatomegaly, anaemia, hypoglycaemia and disturbance
of amino acid metabolism have been seen in some PNPO
deficiency patients (Ruiz et al. 2008). To date, there have been
less than 50 cases reported world-widely (Coman et al. 2016).
Here, we report 4 Chinese patients genetically diagnosed as
PNPO deficiency, and find some novel atypical clinical presentations among them.

Severe delay

PNPO mutations (NM_018129) Psychomotor
development

Metab Brain Dis

Metab Brain Dis

respectively. Before the premature onset of labor, the pregnancy was uneventful. Labored and irregular breathing, and cold
extremities were observed after birth in both, Apgar scores
were 5–9-9 and 7–9-9 (at 1, 5 and 10 min) respectively.
The clinical manifestations of them were pretty similar.
Seizures started within 24 h after birth and manifested as clusters of a sudden shouting with limbs stiff lasting for 1–2 s,
which were speculated as myoclonus or spasms. Along with
the progress of the disease, focal seizures, definite spasms and
generalized tonic-clonic seizures were observed. Several
kinds of AEDs, including phenobarbital, valproic acid, clonazepam, topiramate and levetiracetam were used in monotherapy or combination without seizure remission. Then, pyridoxine was used continuously in both patients from the age of
1 month, which obviously reduced the frequency of seizures
from more than 10 times to 3–4 times a day. No temporary
respiratory depression was observed during pyridoxine treatment. In the next few years, various AEDs were tried together
with pyridoxine, without seizure control. From the age of
5 years, pyridoxine (300 mg/d) was used alone. Focal seizures
were observed with a frequency ranging from one time per
month to 3–4 times per day. At the age of 6 years 4 months,
they were diagnosed as PNPO deficiency by gene analysis.
Then PLP (30 mg/kg/d) was used instead of pyridoxine.
Seizures worsened for the first few days after using PLP in
both of them and returned to a similar frequency as before
gradually. At the same time, due to the obvious side effects
of PLP including frequent vomiting and poor appetite, pyridoxine was used again to replace PLP. At the last follow-up
(6 years 9 months), seizures still existed in both. Their psychomotor development were severe delayed. They could sit
independently, but could not speak, stand or walk.
Patient 3
Patient 3 was the second child of healthy non-consanguineous
parents and had a healthy sister. He was born at term with a birth
weight of 3800 g. Both the pregnancy and delivery were unremarkable. A seizure was first observed during a fever at the age
of 5 months, manifesting as sudden loss of consciousness, staring, convulsive movements of limbs with fists clenched, teeth
clenched and drooling, lasting 5 min approximately. No treatment was given at that time. Then, seizures aggravated gradually
with a frequency of 1–2 times per month and were more frequently during infectious or febrile diseases. Valproic acid was
used and no seizures were observed for about 7 months. Then
seizures recurred and could not be controlled by adding other
medicines such as phenobarbital, oxcarbazepine, carbamazepine
and levetiracetam. At the age of 3 years 10 months, he was
diagnosed as PNPO deficiency by gene analysis. Under a seizure
frequency of 1–2 times per month, pyridoxine (180 mg/d, 10 mg/
kg/d) was used together with valproic acid and oxcarbazepine,
then seizures disappeared for two months. Whereafter, valproic

acid was withdrawn gradually and he has remained seizure-free
for more than 6 months to present. The next step, oxcarbazepine
would be withdrawn. Gesell developmental scale assessment
showed borderline to mild delay at 3 years 10 months, presenting
borderline (76 ≤ DQ ≤ 85) in fine motor, and mild delay
(55 ≤ DQ ≤ 75) in adaptability, gross motor, language and personal and social competence.
Patient 4
Patient 4 was the first child of healthy non-consanguineous
parents with one spontaneous abortion history. He was born at
term without problems. Feeding intolerance presented in the
neonatal period. Seizures started at 40 days after birth, manifesting as elevation and rigidity of both legs during sleep,
lasting about 20 s. Then, a manifestation of head turning to
left with a stiff neck was observed during awake period, lasting about 20 s also. When he was 4 months old, convulsive
symptoms closely following the above manifestations occurred, presenting as bilateral limbs twitching, ocular deviation, facial cyanosis, teeth and fists clenched, lasting 1 min
approximately. The seizure frequency was from once every
4 months to 2–3 times per day. Without antiepileptic treatment, the frequency of seizures increased to 7–9 times per
day at 10 months. Then valproic acid was used and seizures
were controlled for nearly 2 years. When the seizures relapse,
the dosage of valproic acid was increased (55 mg/kg/d) without effecacy and then topiramate was added (2.5 mg/kg/d).
Seizures were controlled for more than 3 years under the
above treatment and recurred again at 5.5 years old, which
disappeared again after increasing the dosage of valproic acid
(54 mg/kg/d) and topiramate (2.5 mg/kg/d). Up to the confirmation of PNPO deficiency (7.5 years old), he had no seizures
for 2 years with the treatment of valproic acid (36 mg/kg/d)
and topiramate (2 mg/kg/d). But considering the specific effect of PLP or pyridoxine on this syndrome, pyridoxine
(180 mg/d, 6 mg/kg/d) was still added to the previous
AEDs. During the short-term follow-up of 6 months, no side
effects or relapses were observed. Next, whether or not the
AEDs should be continued will be discussed according to the
condition of seizure control and the will of parents. He had
development delay since birth. He could sit from 1 year old,
and walk from 2 years old. At the last follow-up (8 years old),
he could not speak or self-care.
EEG, MRI and metabolic investigation
For patient 1 and 2, EEG showed multifocal epileptiform discharges at 7 months in both (Fig. 1a-b), and showed atypical
hypsarrhythmia or posterior multifocal discharges respectively at 15 months (Fig. 1c-d). Several EEG examinations of
patient 3 showed slow background activity with multifocal
epileptiform discharges (Fig. 2). The only two EEGs of patient

Metab Brain Dis

Fig. 1 EEGs of patient 1 and patient 2. EEGs at 7 months: a sharp and
slow waves in left anterior and right occipital and temporal areas in
patient 1; and b spikes and spike waves in bilateral frontal and central

regions in patient 2. EEGs at 1 year and 3 months: c atypical
hypsarrhythmia in patient 1; and d spikes, spike waves and slow waves
in posterior primarily in patient 2

4 at the age of 4 months and 10 months all showed normality
during interictal periods. MRI showed periventricular white
matter attenuation, bilateral ventricles widened mildly, sulci of
frontal and temporal widened in the twins (at 15 months), and
was normal in patient 3 and patient 4.
Blood metabolic screening showed obviously decreased
arginine (3.76 and 2.39 umol/L, normal range: 5–40

umol/L), aspartic acid (7.35 and 9.24 umol/L, normal range:
20–120 umol/L) and methionine (6.63 and 9.15 umol/L, normal range: 10–50 umol/L) in patient 1 and 2 respectively;
showed mild elevated leucine (342 umol/L, normal range:
50–290 umol/L) and valine (306.5 umol/L, normal range:
60–290 umol/L) in patient 3; and showed mild decreased threonine (19.8 umol/L, normal range: 22–200 umol/L) in patient

Fig. 2 EEG of patient 3 showed
spikes and spikes waves in
bilateral frontal, right central, and
midline area of frontal and central
regions

Metab Brain Dis

4. Urinary metabolic screening showed vanillactic acid
(VLA) marketly elevated in patient 1, 2 and 4 (44.8,
32.94 and 107.64 mmol/mol creatinine respectively, normal mean value: 0.9 mmol/mol creatinine), and was
normal in patient 3.

Gene mutation analysis
Molecular genetic analysis revealed compound heterozygous
mutations of PNPO gene (NM_018129) in all patients, including c.445_448del (p.Pro150ArgfsTer27) and c.481C > T
(p.Arg161Cys) in the twins (Fig. 3); c.445_448del and
c.413G > A (p.Arg138His) in patient 3 (Fig. 4); c.148G > A
(p.Glu50Lys) and c.347G > A (p.Arg116Gln) in patient 4
(Fig. S1). No other gene variant was found in the genes represented on the panel. The parents of each patient had been
available for testing and proved the autosomal recessive inheritance. All mutations were not detected in 100 control samples. Based on the Human Gene Mutation Database (HGMD),
the pathogenicity of c.148G > A and c.347G > A had been
reported in PNPO deficiency, and c.413G > A, c.481C > T and
c.445_448del had never been reported before. All the 4 missense mutations here affected evolutionarily conserved residues (Fig. S2). The effects of c.148G > A and c.347G > A on
PNPO activity were proved by Mills et al. (2014), decreasing
PNPO activity by ~30% and ~20% respectively. The novel
mutations c.413G > A and c.481C > T were predicted by
PolyPhen-2 to be Bprobably damaging^ on protein function
with a probabilistic score of 1.000 in both, and predicted by
MutationTaster to be Bprobably deleterious^.

Fig. 3 PNPO gene analysis of patient 1, 2 and their parents: c.445_
448del inherited from their father, and c.481C > T inherited from their
mother

Fig. 4 PNPO gene analysis of patient 3 and his parents: c.445_448del
inherited from his mother, and c.413G > A from his father

Discussion
Dietary vitamin B6 enters the blood stream as pyridoxine,
pyridoxamine and pyridoxal. Pyridoxine and pyridoxamine
are converted to the active cofactor PLP through the activity
of a kinase and then of PNPO (McCormick and Chen 1999).
Dysfunction of PNPO leads to a deficiency of PLP and subsequently to epileptic seizures, the most common and cardinal
symptom of PNPO deficiency. In this study, we report 4 cases
diagnosed as PNPO deficiency clinically and genetically.
At present, some suggestive clinical presentations has been
reported in patients with PNPO deficiency. For example, prematurity appeared in more than half of the patients; About
61% patients presented with seizures on the first day of life
and 96% before 1 month; And myoclonus was the most common seizure type, and burst suppression in EEG was reported
in 57% patients (Levtova et al. 2015). Consistently, the twins
here had similar clinical presentations. They were premature
and suffered from seizures during the first 24 h. A suspicious
myoclonus was supposed by the clinical manifestations,
though the EEG data at that time was unavailable. In addition,
the twins had a sign of encephalopathy after birth, including
labored and irregular breathing, and cold extremities.
However, because these presentations could be observed in
both birth asphyxia and some PNPO deficiency cases (Hatch
et al. 2016), when we looked back to that, it was hard to
discern whether it was due to true asphyxia or PNPO deficiency. None of the above presentations presented in other 2 patients, who were born at term and started seizures at 5 months
and 40 days respectively. The later onset of seizures had been
reviewed by Guerin et al. (2015) that 7% of the patients presented with late neonatal onset (up to 3 weeks of age), and 5%
of the patients presented with early infantile onset (up to
5 months of age). Moreover, during the courses of these 2

Metab Brain Dis

patients, no myoclonic seizures occurred. Patient 3 was prone
to seizures during fevers or infectious diseases, which was a
feature commonly seen in pyridoxine dependent epilepsy
(PDE) (Stockler et al. 2011; Xue et al. 2015), but was only
reported in a few PNPO deficiency patients previously
(Sudarsanam et al. 2014). Besides, patient 4 had frequent seizures easily controlled by AEDs, and the interictal EEG always showed normality. The normality of EEG was reported
in only one PNPO deficiency patient before using PLP treatment by Hoffmann et al. (2007), but was reported in some
patients with PDE (Xue et al. 2015).
PNPO deficiency was once described as neonatal seizures
responding to PLP only. However, as the number of confirmed cases increased, the phenotype expanded to three subgroups: early-onset neonatal seizures responding to PLP; infantile spasms responding to PLP; and seizures beginning under 3 months of age and responding to pyridoxine (Mills et al.
2014). The twins here had a similar disease courses to the first
subgroup above. But they had only partial response to both
PLP and pyridoxine. A transient aggravation of seizures at the
initial using PLP was observed in them, which might be because PLP had a strong inhibitory effect on PNPO activity and
mutant PNPO protein might be inhibited by the administration
of PLP (Plecko et al. 2014). One patient (patient 3) with onset
of seizures at the age of 5 months here had a good response to
pyridoxine, which expanded the onset age of seizures in the
third subgroup. The mechanism of pyridoxine responsiveness
is still unclear. A hypothesis proposed that the mutations carried by these patients had a small perturbation
to the configuration of PNPO, allowing some pyridoxine
phosphate being oxidized to PLP (Ware et al. 2014).
However, Mills et al. (2014) reported that the same
combination of mutations could be seen in both patients
responding and not responding to pyridoxine, which
suggested that pyridoxine responsiveness must be affected by some other factors, such as the age at the therapeutic trial. In addition, we found a relatively good
response to AEDs in patient 4, who was controlled by valproic
acid alone or combined with topiramate for 2 and 3 years
respectively. Due to the good control of seizures by AEDs,
there was no chance to identify the effect of pyridoxine. This
might be a novel phenomenon in PNPO deficiency, but the
mechanism is still unknown.
Up to now, more than 24 different disease-causing PNPO
mutations have been reported, with the most common being
missense/nonsense mutations (Veeravigrom et al. 2015). Here,
we identified 5 different mutations, including 4 missense mutations and one deletion mutation. Among them, the novel
mutation c.445_448del was expected to cause a frameshift
in the protein sequence after Pro150, altering the next 27 amino acids before introducing an early stop codon, and further
inducing a significant reduction in the PNPO activity. Its pathogenicity could be supported by the mutation c.448_451del

reported by Guerin et al. (2015), which induces a similar
change of amino acids (p.Pro150ArgfsTer27) with
c.445_448del. This frameshift mutation identified in 3 of 4
patients here might indicate a possible high prevalence mutation in Chinese patients. The identical twin brothers carrying
complete same mutations had very similar clinical characteristics, while the other patients had extremely different phenotypes. This suggested that the phenotype might be influenced,
even decided, by the different genotypes. However, due to the
limited number of cases up to now, further studies are needed
to reveal the genotype-phenotype correlations in PNPO
deficiency.
PLP is the cofactor for >140 enzyme-catalyzed reactions
(Mills et al. 2014). The secondary dysfunction of PLPdependent enzymes lead to abnormalities of amino acid, neurotransmitter and metabolites in cerebrospinal fluid (CSF),
plasma or urine. Elevated glycine and threonine, and reduced
arginine in plasma and CSF, as well as increased urinary VLA
levels, had been reported in PNPO deficiency (Kuo and Wang
2002; Veeravigrom et al. 2015). However, these biomarkers
were not specific, which were normal or even contrary to the
descriptions above in some patients (Bagci et al. 2008; Khayat
et al. 2008; Ware et al. 2014; Hatch et al. 2016). In our study,
decreased plasma arginine and threonine, and elevated urinary
VLA were confirmed again. In addition, decreased plasma
aspartic acid and methionine, and elevated leucine and valine
were also found, which were not reported in the literature. The
mechanisms of these different plasma amino acids profiles are
not clear yet. One possible explanation was that the level of
plasma amimo acids might be more easily influenced by dietary intake and other factors. However, due to the condition
limitations, its levels in CSF were not detected, which should
be conducted in the future to confirm the hypothesis. Another
possibility, the concentrations of metabolites above were decided by genotypes, that is to say, different gene mutations
disturbed different functional domains of PNPO, leading to
dysfunction of PLP-dependent enzymes in different types
and severity.
As many rare diseases, it is difficult to assess the long-term
outcome of PNPO deficiency. Various clinical outcomes have
been reported, ranging from normal to severe development
delay, even early death if left untreated. Patients who were
diagnosed and treated appropriately earlier were more likely
to have favorable outcomes (Veeravigrom et al. 2015). Three
patients (twins and patient 4) in our study had severe development delay. For the twins, to some extent, it could be considered that intractable seizures might played a bad role on the
poor outcomes. However, the above explanation might not be
applied to patient 4, because only a relatively small number
seizures occurred during his disease course. Besides, though
experiencing a more than 3 years delay in controlling seizures
with pyridoxine, patient 3 had only borderline to mild rather
than severe development delay. All the above suggested that

Metab Brain Dis

other than prompt treatment, some other factors such as genotypes might affect the disease severity also.

Conclusions
We reported 4 Chinese patients with PNPO deficiency here.
The clinical characteristics of them differed greatly, including
typical presentations but incomplete response to pyridoxine or
PLP, later-onset seizures with a good response to pyridoxine,
and seizures controlled by one or two kinds of AEDs for a few
years, which expands the phenotypes of this syndrome.
Besides, three novel mutations were found in this study, including the frameshift mutation c.445_448del identified in 3
of 4 patients, which might be high prevalence in PNPO deficiency in Chinese patients.
Acknowledgments
participating.

We thank the patients and their families for

Compliance with ethical standard The study was approved by the
ethics committees of the Peking University First Hospital. For the genetic
studies, written permissions were obtained from all patients’ parents or
guardians.
Funding This research was supported by grants from Beijing key laboratory of molecular diagnosis and study on pediatric genetic diseases
(No: Z141107004414036).
Conflicts of interest The authors declare that they have no conflict of
interest.

References
Bagci S, Zschocke J, Hoffmann GF et al (2008) Pyridoxal phosphatedependent neonatal epileptic encephalopathy. Arch Dis Child Fetal
Neonatal Ed 93(2):151–152
Coman D, Lewindon P, Clayton P et al (2016) PNPO deficiency and
cirrhosis: expanding the clinical phenotype? JIMD Rep. 25:71–75
Guerin A, Aziz AS, Mutch C (2015) Pyridox(am)ine-5-phosphate oxidase deficiency treatable cause of neonatal epileptic encephalopathy

with burst suppression: case report and review of the literature. J
Child Neurol 30(9):1218–1225
Hatch J, Coman D, Clayton P et al (2016) Normal neurodevelopmental
outcomes in PNPO deficiency: a case series and literature review.
JIMD Rep 26:91–97
Hoffmann GF, Schmitt B, Windfuhr M et al (2007) Pyridoxal 5′-phosphate may be curative in early-onset epileptic encephalopathy. J
Inherit Metab Dis 30(1):96–99
Khayat M, Korman SH, Frankel P et al (2008) PNPO deficiency: an
under diagnosed inborn error of pyridoxine metabolism. Mol
Genet Metab 94(4):431–434
Kuo MF, Wang HS (2002) Pyridoxal phosphate-responsive epilepsy with
resistance to pyridoxine. Pediatr Neurol 26(2):146–147
Levtova A, Camuzeaux S, Laberge AM et al (2015) Normal cerebrospinal fluid Pyridoxal 5′-phosphate level in a PNPO-deficient patient
with neonatal-onset epileptic encephalopathy. JIMD Rep 22:67–75
McCormick DB, Chen H (1999) Update on interconversions of vitamin
B-6 with its coenzyme. J Nutr 129(2):325–327
Mills PB, Surtees RA, Champion MP et al (2005) Neonatal epileptic
encephalopathy caused by mutations in the PNPO gene encoding
pyridox(am)ine 5′-phosphate oxidase. Hum Mol Genet 14(8):1077–
1086
Mills PB, Camuzeaux SS, Footitt EJ et al (2014) Epilepsy due to PNPO
mutations: genotype, environment and treatment affect presentation
and outcome. Brain 137(5):1350–1360
Plecko B, Paul K, Mills P et al (2014) Pyridoxine responsiveness in novel
mutations of the PNPO gene. Neurology 82(16):1425–1433
Ruiz A, García-Villoria J, Ormazabal A et al (2008) A new fatal case of
pyridox(am)ine 5′-phosphate oxidase (PNPO) deficiency. Mol
Genet Metab 93(2):216–218
Stockler S, Plecko B, Gospe SM Jr et al (2011) Pyridoxine dependent
epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up.
Mol Genet Metab 104:48–60
Sudarsanam A, Singh H, Wilcken B et al (2014) Cirrhosis associated with
pyridoxal 5′-phosphate treatment of pyridoxamine 5′-phosphate oxidase deficiency. JIMD Rep. 17:67–70
Veerapandiyan A, Winchester SA, Gallentine WB et al (2011)
Electroencephalographic and seizure manifestations of pyridoxal
5′-phosphate-dependent epilepsy. Epilepsy Behav 20(3):494–501
Veeravigrom M, Damrongphol P, Ittiwut R et al (2015) Pyridoxal 5′phosphate responsive epilepsy with novel mutations in the PNPO
gene: a case report. Genet Mol Res 14(4):14130–14135
Ware TL, Earl J, Salomons GS et al (2014) Typical and atypical phenotypes of PNPO deficiency with elevated CSF and plasma pyridoxamine on treatment. Dev Med Child Neurol 56(5):498–502
Xue J, Qian P, Li H et al (2015) A cohort study of pyridoxine-dependent
epilepsy and high prevalence of splice site IVS11+1G>a mutation in
Chinese patients. Epilepsy Res 118:1–4
Xue J, Li H, Zhang Y et al (2016) Clinical and genetic analysis of two
Chinese infants with Mabry syndrome. Brain Dev 38(9):807–818