PNPO deficiency

Roma, 17/10/2015
Dipar$mentodiPediatriaeNeuropsichiatriaInfan$le
Ges$onedelleemergenzenellemala/e
metaboliche
VincenzoLeuzzi
The Metabolic (and Molecular) Bases of Inherited Disease
Scriver, Beaudet, Valle, Sly
McGraw-Hill
Child, Kinzler, Vogelstein
1960 1966 1972 1978 1983
<1000 pp
1989
1995
2001
>6000 pp
2001 >
∞
Errori Congeniti del Metabilismo (ECM)
Classificazione degli ECM
•  Gruppo 1. Malattie che compromettono il metabolismo di
molecole complesse
•  Gruppo 2. Errori congeniti del metabolismo intermedio
(disease of the intoxication type)
•  Gruppo 3. Errori congeniti del metabolismo energetico
J.M. Saudubray, 2001
Epidemiologia degli ECM
nell’infanzia
•  Applegarth et al. Incidence of inborn errors of
metabolism in British Columbia, 1969-1996.
Pediatrics, 2000;105:1-6.
•  Dionisi-Vici et al. Inborn errors of metabolism in the
Italian pediatric population: a national retrospective
survey. J Pediatr, 2002;140:231-7.
•  Sanderson et al. The incidence of inherited metabolic
disorders in the West Midlands, UK. Arch Dis Chil
2006;91:896-9.
Epidemiologia degli ECM nell’infanzia
(Sanderson et al., 2006)
Malattie metaboliche: età alla diagnosi
Sanderson et al., 2006
Malattie metaboliche: età alla diagnosi
Sanderson et al., 2006
Trattamento etiologico delle ECM
•  Rimozione metaboliti tossici
•  Restrizione del substrato
•  Attivazione di pathways alternativi
•  Inibitori metabolici
•  Reintegrazione dei metaboliti carenti
•  Interventi a livello della proteina deficitaria
•  Attivazione tramite cofattore vitaminico
•  Terapia sostitutiva (protein replacement therapy)
•  Trapianto d’organo
•  Trapianto di midollo osseo
•  Terapia genica
ECM ad esordio acuto
“…the unexpected and mysterious
deterioration of a child after a normal
initial period is the most important signal
of the presence of an inherited disease of
the intoxication type”
J.M. Saudubray, 2001
Principali pattern di acuzie clinica
•  deterioramento neurologico
•  con epilessia (es, B6 def, NKH, GAMT def, ...)
•  senza epilessia (UCDs, BCOAs, MSUD)
•  insufficienza epatica (es. galattosemia, tirosinemia
tipo I, ...)
•  insufficienza cardiaca (es. FAO, malattia di
Pompe, ...)
Principali pattern di acuzie clinica (trattabili in modo
specifico )nel neonato
1. Neurological deterioration (metabolic encephalopathy):
Maple syrup urine disease (MSUD), branched-chain organic acidurias
(BCOAs) and urea cycle defects (UCDs).
2. Liver failure: Galactosaemia, hereditary fructose intolerance
and tyrosinaemia type I.
3. Hypoglycaemia: hyperinsulinism, glycogen storage disease (GSD) and
mitochondrial fatty acid oxidation (FAO) defects.
4. Cardiac failure: In neonates the only treatable disorders are FAO defects.
5. Primary hyperlactataemia: lack of cellular energy and may be due to different
enzymatic defects. Some patients may benefit from high-dose vitamin treatment.
6. Intractable convulsions: Vitamin responsiveness (pyridoxine,
pyridoxal phosphate, folinic acid, biotin).
Deterioramento neurologico senza epilessia
nel neonato
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intervallo libero ore/giorni
difficoltà di suzione e deglutizione
coma
segni da interessamento neurovegetativo
anomalie respiratorie
singhiozzo
bradicardia
ipotermia
episodi di ipertono/opistotono
boxing or pedaling movements
ipotono assiale/ipertono degli arti
tremore ad elevata ampiezza/myoclonic jerks
ipotonia generalizzata
Deficit neurologici acuti nel bambino e nell'adolescente
neurologicalsigns
diseases
coma
UDCs,BCOAs,MSUD,FAO,GA-1,mul3plecarboxylasedef,hyperinsulinism
seizures
NKH,B6metabolismdef,GAMTdef,Minkesdeseases,OXPHO,GLUT1,Lys(GaucherIII,NPC),
UDCs,BCOAs,MSUD,FAO,GA-1,mul3plecarboxylasedef,hyperinsulinism,etc
oculogyriccrysis
neurotransmiOersdis;PKU
ataxia
MSUD,PDH,UCDs,mul3plecarboxylase,B12defects,GLUT1,SSDAH,Thiamineresponsive
encephalop,...
dystonia
BCOAs,AG-1,Wilsond,aceruloplasm,bio3nresponsivebasalgangliadisease,GAMT,Hct,
Lesh-Nyhan,...
stroke-like
OXPHOS(MELAS),OCT,Hct,CDGs,OAs,Fabry,beta-ketothiolase,...
demen$a
acereruloplasmine,Wilsond,alphamannosidase,X-ALD,porphyria,bio3nidasedef,...
suddenhearingloss
MELAS
suddenvisualloss
MELAS,Leber,MMA,PA,Hct,X-ALD,porphyria,bio3nidasedef,
pain
Fabry,Gaucher,Krabbe,prolidasedef,
acuteperipheralneuropathy
PDH,bio3nidase,MLD,MSUDvariant,tyrosinemiatypeI,LCHAD/MTP
hydrocephalus
MPSI,II,IV,Cbl-C,Cbl-D,MTHFR,Gaucher,NKH,mannosidosis
myoglobinuria
FAO,muscleGSD,OXPHOS,LIPIN1,porphyria,Wilsond
cramps
FAO,muscleGSD
Emergency diagnostic procedures
First line diagnostic tests (bedside)
•  general clinical chemistry
•  complete blood count, CRP, electrolites, liver and kidney function tests
•  baseline metabolic screen tests
•  blood gas +anion gap
•  lactate
•  glucose
•  ammonia
•  uric acid
•  CK
•  urinary ketones
•  urinary reducing substances
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Second-line investigations (by 24-48 hours)
blood/plasma acylcarnitine
plasma amino acids
urinari organic acids
urinary orotic acids
conditional additional tests:
•  gal-1-p; GALT (suspected galactosemia)
•  free fatty acids, 3-hydroxybutyrate, insulin (sispected
hyperinsulinism)
•  purine analysis (suspected disorders of purine metab)
Emergency scenarios
• Hyperammoniemia
• Metabolic acidosis
• Hypoglicemia
Assessment of intermediary metabolism over the course of the day
COMA
Saudubray, 2011
COMA
Saudubray, 2011
Emergency treatment
•  Supportive care
circulatory and ventilatory support,
rehydratation, correction of mineral and/or electrolyte imbalance (Ca,
Mg, P), prevent and treat infections
Hyperammonia
•  stop protein intake
•  intravenous glucose (to stop catabolic status)
•  if hyperglycemia à insulin (not reduce glucose infusion)
•  detoxication of ammonia:
•  Benzoate (250mg/kg/day in 4-6 div doses)
•  Phenylbutirate (250mg/kg/day in 4-6 div doses)
•  Arginine (250mg/kg/day in 4-6 div doses) (not in
hyperargininemia)
•  N-carbamylglutamate
•  extracorporeal detoxification
Hyperammonia (UCD, OA: MMA, PA, IVA)
Cagnon & Braissant, 2007
Ogier de Baulny, Dionisi-Vici, Wendel
Acidosis
(base deficit>8mmol/l)
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if dehydrated à saline 0.9% (20 ml/kg)
glucose 200 mg/kg at once (2 ml/kg of 10% glucose) over a few minutes
continue with glucose 10% saline 0.45% at 5 ml/kg/h.
if acidosi is still not corrected à sodium bicarbonate 8.4% over 20-30'
•  blood gases over 30 min
•  continuous bicarbonate infusions
Carnitine
Vitamins:
•  B12 à MMA (nutrizional B12 defect, Cblc)
•  Biotin (holocarboxilase dehydrogenase synthetase)
•  Thyamine (lactic acidosis)
•  Riboflavine (MADD)
Hypoglicemia (blood glucose < 2.6mmol/l)
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lactate
free fatty acids
insulin
cortisol
blood spot
blood spot acylcarnitine profile
plasma amino acids
uric acid
urine ketones
urine organic acids
dextrose 10 % 5 bolus 2 ml/kg à continue with infusions (3-6
ml/kg/h)
Earlyonsetmetabolicepilep$cencephalopathies
treatable
untreatable
amino-andorganicacidopathies
typicalphenylketonuria
nonketo$chyperglycinemia
serinebiosynthesisdefects
AGC1(SLC25A12)deficiency;GC1(SLC25A22)deficiency
D-2hydroxyglutaricaciduria;ethylmalonicacididuria(ETH1)
cofactordisturbances
bio$nasedeficiency
isolatedsulfideoxidasedeficiency
BH4metabolismdefects
molybdenumcofactordeficiency(typeB)
pyridoxine/pyridoxal-phosphate–dependentepilepsy(folinicacidrespSeiz)
Menkesdisease
molybdenumcofactordeficiency(typeA;MOCS1)
Cerebralfolatedeficiency(CFD):DHPR,FORL1
inbornerrorsofenerge$cmetabolism
GLUT1defect
crea$netransportdefect(males)
crea$netranspor(femalecarriers)andcrea$nesynthesis(GAMT)defects
mitochondiopathies
peroxysomaldisorders
Zellwegersyndrome,neonatalALD
lysosomaldisorders
neuronalceroidlipofuscinoses,gangliosidioses,sialidosis
disordersofneurotransmi\ers
GABAtransaminanasedeficiency
congenitaldisordersofglycosila$on
CDGIc,Ik,II
disordersofpurinemetabolism
adenylosuccinatelyasedefect
B6-dependency:brainMRI
Shihetal,1996
B6-dependency:progressivebrainatrophy
10
days
4
years
Gospe&Hecht,1998
B6-dependency:brainGPET1996
Shihet.al.,1996
7.5years:Isolatedthinningofposteriorregionof
corpuscallosum
Rankinetal,2007
Pyridoxine/PLP dependent seizures
L-Proline
-
-
P5C
P5C-dehydrogenase
L-Lysine
P6C
AASA dehydr
Garcia-Cazorla, Gibson, Clayton, 2012; modified
Inborn errors and vitamin B6 dependent epilepsy
increased utilixation of PLP
TYPE II
HYPERPROLINEMIA
(? febrile) seizure onset
infancy to childhood
± response to common
antiepileptic drugs
± mental retardation
ANTIQUIN
DEFICIENCY
neonatal onset of myoclonic seizures
resistence to common
anticonvulsivants
30% poor adaptation/ HI
30% signs of encephalopathy
prematurity
systemic manifestation (abd
distension, vomiting..)
Proline metabolism
An$qui$nandB6-dependency
pathogenesis
α-AASDH
Clayton,2006
The phenotype of B6-dependent epilepsy
•  incidence: 1/20.000 – 1/750.000 (marked geographical variation)
•  autosomal recessive transmission
•  typical presentations
–  refractory seizures in neonate; often prenatal seizures with secondary asphyxia
–  multiple seizure types focal, generalized, atonic, myoclonic, infantile spasms,
severe sudden epileptic status;
–  newborn encephalopathy:
•  Jitteriness, hypothermia, dystonia
•  restlessness, irritability, and emesis preceding the seizures
–  only remit with pyridoxine
–  progressive encephalopathy if not promptly treated
•  atypical presentation and course
–  late onset (< 19 months)
–  partial or transient responsiveness to conventional antiepileptic therapy (Lin et al,
2007)
–  transient unresponsiveness to B6 treatment (Claus et al, 2003)
–  protract seizures free interval after B6 discontinuation (Baxter 2003, Gospe 2002)
•  prenatal examination: progressive bilateral
asymmetric ventriculomegaly
•  > 7 days: multifocal clonic and generalized
tonico-clonic seizures
•  > 21 days: pyridoxine (14 mg/kg/day) à no
further seizures
•  2 months pyridoxine discontinuation à
seizures recurrence à pyridoxine
reintegration (30 mg/kg/day)
•  urine AASA: 30.6 mmol/mol creat; r.v. 0.0-2)
•  ALDH7A1 gene: p.Ala149Glu/Arg307X
•  7 months: no seizures, normal development,
normal EEG
- 13-month old girl
- profound neonatal hypoglycemia, lactic acidosis
- MRI: bilateral temporal lobe hemorrhages, thalamic
changes
- multifocal and myoclonic seizures refractory to
multiple antiepileptic drugs that responded to
pyridoxine (200 mg/day)
- ALDH7A1 gene: c.834G.A (p.Val278Val)/c.1192G.C
(p.Gly398Arg)
- Urinary a-AASA: 21.3 mmol/mol creatinine (r.v. < 1)
- CSF pyridoxal phosphate 3.6 nmol/L (r.r.: 30–80)
EEG:hypsarrhythmiabeforeB6
Clausetal,2003
Clausetal,2003
1month,mul$focalmyoclonicepilepsy
Linetal,2007
Treatment
•  Normalpyridoxineintake:8μg/kg/day
•  Pyridoxine
–  op3maldosageforlifelongmaintenance:∼15mg–50mg/kg/day(max500mg/day)
–  pregnantwomen(prenataltreatment)50-100mg/day(Baxter,2003)
–  noadversesideeffectsupto24mg/kg/day(Baxter,2002);monitorNC(Rankin,2007)
• 
Pyridoxineintoxica$on:dorsalrootganglionopathy(painfulneuropathy),sensoryataxia,possiblemotor
neuropathy,rash,photosensi3vity.
• 
Treatmentmonitoring: –  EEGandclinicalexamina3on –  α-AASAandpipecolicacidarenotalteredbythetreatment(Bok,2007)
• 
Lysinerestricteddiet(20-100mg/kg/day)(vanKarnebeeketal,2012;2014)
–  êα-AASA,pipecolic,lysineinbiologicalfluids
Pyridoxine/PLP dependent seizures
AOX (MoCof)
Pyridoxic acid
(urine)
Garcia-Cazorla, Gibson, Clayton, 2012; modified
Inborn errors and vitamin B6 dependent epilepsy
increased utilixation of PLP
TYPE II
HYPERPROLINEMIA
ANTIQUIN
DEFICIENCY
reduced synthesis of brain PLP
PNPO
DEFICIENCY
INFANTILE TNSALP
DEFICIENCY
(hypophosphatasia)
MABRY
SYNDROME
(PIGV gene)
hyperphosphatasia
seizure onset infancy to
childhood
± response to common
antiepileptic drugs
± mental retardation
neonatal onset of myoclonic seizures
hypophosphatasia
resistence to common anticonvulsivants
neonatal seizures in
lethal neonatal or
infantile forms
dysmorphy
mental retardation
prematurity
resistance to
common
antoconvulsivants
systemic manifestation (abd distension,
vomiting..)
death due to resp.
insufficiency
30% poor adaptation/ HI
30% signs of encephalopathy
floppy infant
brachy-telefalangy
seizures
rickets
Inclusion
body (PASpos)
Inborn errors and vitamin B6 dependent epilepsy
increased utilixation of PLP
TYPE II
HYPERPROLINEMIA
(? febrile) seizure onset
infancy to childhood
± response to common
antiepileptic drugs
± mental retardation
ANTIQUIN
DEFICIENCY
reduced synthesis of brain PLP
PNPO
DEFICIENCY
INFANTILE TNSALP
DEFICIENCY
(hypophosphatasia)
neonatal onset of myoclonic seizures
neonatal seizures
- in lethal neonatal
or infantile forms
resistence to common
anticonvulsivants
30% poor adaptation/ HI
MABRY
SYNDROME
(hyperphosphatasia)
resistance to
common
antoconvulsivants
30% signs of encephalopathy
prematurity
death due to resp.
insufficiency
systemic manifestation (abd
distension, vomiting..)
Thompson et al, 2010
PNPOdeficiency:earlysymptoms
no.ofcases
fetalseizures
3/16
fetaldistresspriortodelivery
5/16
prematurebirth/lowAPGARscore/intuba$onatdelivery
5/16
onsetofseizures<24h
11/14
24-72h
2/14
72h-2weeks
1/14
burstsuppressionpa\ern(EEG)
10/11
drug-resistentseizures
13/16
pyridoxine-resistenfseizures
7/10
acidosis
6/16
lac$cacidosis
8/16
distressingdystonicspasms
3/16
anemia
3/16
hepatomegalia
3/13
abdominaldistension
2/16
hypoglycaemia
2/16
Garcia-Cazorla, Gibson, Clayton, 2012
Mills et al, 2014
Mills et al, 2014
Treatment of PNPO defect
PLP (Pyridoxal-5-phosphate responsive patients)
10-53 mg/kg/day; 4-6 divided doses/day
Pyridoxine (Pyridoxine-responsive patients)
5.5-50 mg/kg/day; 2-4 divided doses/day
? Riboflavin (? according to PNPO genotype)
100 mg /day
Advers events
peripheral neuropathy (pyridoxine > PLP) (? > 200 mg/day)
liver toxicity (cirrhosis, hepatic fibrosis): high PLP dosages (100 mg/kg) (Mills et
al, 2012); 1000 mg/day (Yoshida et al., 1985 in homocystinuria ).
Patterns of therapeutic response and PNPO genotypes
treatmentresponse
PNPOgenotype
Ref
pa$entsrespondingtoPLP
E50K/E50K+spliceerror
D33V/D33V
P213S/P213S
R95C/R95C
Q214fs/?
R116Q/R116Q
R229W/R229W
X262Q/X262Q
R229Q/P229Q
A174X/A174X
R95H/R95H
Millsetal,Brain2014
Millsetal,HumMolGenet,2006
Millsetal,HumMolGenet,2006
Wareetal,DMCN2013
Ruizetal,MolGenetMetab2008
Khayatetal,MolGenetMetab2008
pa$entsrespondingto
pyridoxine(poten3ally
worseningunderPLP)
R116Q/R116Q
D33V/D33V
D33V/E120K
D33V/spliceerrors
D33V+R225C+R116Q
R225H/R225H
R225H;R116Q+R225H;R116Qc
R225H;R116Q+R225H;R116Qc
R141C/c.279_290del
G118R/G118R
Millsetal,Brain2014
Pleckoetal,Neurology2014
Pearl,JMDr2013
pa$ent(s)respondingto
pyridoxineplusriboflavine(B2)
D33V+R225C+R116Q
Millsetal,Brain2014(pt.12Mills2014)
?suscep$bilityalleletoPLPresponsiveepilepsy
R116Q
Millsetal,Brain2014
Clinical Outcome of PNPO defect
- fatal if untreated (a single child surviving with severe epilepsy and psychomotor delay to 3 years of
age - Hoffmann et al., 2007).
- 7 treated cases with PLP: 6/7 survived with varying degrees of disability (1 died as a
result of fungal sepsis (Ruiz et al., 2008).
Mills et al, Brain 2014
CEREBRAL FOLATE DEFICIENCY (CFD)
Serrano et al, 2012
Folate metabolism
Serrano et al, 2012
CEREBRAL FOLATE DEFICIENCY (CFD)
early onset
progressive
encephalopat.
apnoea,
seizure,
hydrocephalus
4 mo:secondary
microcephaly
AED refractory
seizures
Oral Betaine:
100 mg/kg
up to 20 g/day
oral Folinic acid:
1 mg/kg day
Some patients
treated with
5-MTHF
Serrano et al, 2012, mod
DIYDROFOLATE REDUCTASE DEFICIENY
•  related parents
•  4months:generalizedtonic-clonicandright-sided
focalseizuresrefractorytoAEDs
•  secondary microcephaly
•  megaloblastic anemia à pancytopenia
•  plasma: normal Hcyst, folates, B12
•  urine: normal MMA
•  CSF: low 5-MTHF, BH4, HVA, 5-HIAA
•  treatment: oral folinic acid: 30 mg day à
•  19 months: stabilization of seizures under
treatment; severe brain damage
•  DHPR gene: homoz c.238C>T (p.Leu80Phe)
Banka et al, 2011
Urea cycle
gly
Disorders of Cr
metabolism
arg
AGAT
gaa é
orn
Kidney
S-adomet
ATP
GAMT
S-adohcy
Liver
ê Cr
ADP
Cr
CT1
PCr
CK
Muscle, Brain
Cr
Crn
Urinary escretion
Creatine deficiency: clinical findings
Leuzzi et al, 2013
GAMTdeficiency:Clinicalfindingsin34pts
•  Mentalretarda$onandlanguagedisorder 34/34
•  Epilepsy 29/34
•  Au$s$ctraitsandotherbehaviordisorders
23/34
•  Movementdisorders(includingataxia)
20/34
•  Pallidumaltera$onsonbrainMRI 8/29
•  Hypotonia
16/34
•  Lateneurologicaldeteriora$on(?)(CaldeiraAraujoetal,2005)
•  Rare(?)symptoms:microcephaly(2)cirrhosis(1),failureto
thrive(?)
Epilepsy •  Age of onset < 3yrs (range 0-5 yrs)
•  Variable pattern of seizures in the same patient
–  convulsions with fever (at onset)
–  generalized tonic-clonic seizures,
–  drop attacks,
–  absences, non-convulsive status epilepticus
–  life-threatening tonic seizures with apnea,
–  myoclonic seizures,
–  partial seizures with secondary generalization
•  EEG: bilateral or multifocal spikes and slow wave discharges
•  Drug-responsive epilepsy (21/29)
•  Drug unresponsive epilepsy (8/29)
GLUCOSETRANSPORTERPROTEIN
(GLUT1)DEFICIENCY
Defec/veglucosetransportacrossthebloodbrainbarrierasa
causeofpersistenthypoglycorrhachia,seizures,and
developmentaldelay
DeVivoetal,NEnglJMed.,1991,
325:703-709
GLUT1deficiency:clinicalphenotype
Classicphenotype(DeVivophenotype)(≈90%)
–  earlyonset(6.5mesi,r.0.5-77)severeepilep$cencephalopathy
–  secondarymicrocephaly
–  progressivepsychomotorretarda$onàseverementalretarda$on
–  languageretarda$on,
–  clumsiness,
–  pyramidalsigns
–  ataxia
Phenotypicvariants(withoutepilepsyasmainsymptom)
• Carbohydrate-responsivephenotype(Brockmannetal2001,Cigdem2010))
• Mentalretarda$on(MR)andintermi/ngataxia(Overweg-Plandsoenetal2003)
• Mentalretarda$on,behavioraloutbursts,dyskinesias/dystonia/ataxia(Friedmanetal2006)
• Paroxysmal exercise-induced dyskinesias with moderate to severe MR (Zorzi et al
2008)
• Paroxysmalexercise-induceddyskinesiaswithoutorwithmildMR(Weberetal2008;Schneider
etal2008;Sulsetal2008);
• Withhemoly$canemiaandacanthocytosis(Weber et al 2008);
GLUT1deficiency:diagnosis
•  CSF
–  ↓glucose:
•  severeformà30.6±5.4mg/dL(nv60-80mg/dL);
•  mild/lateonsetform41-52mg/dL
–  ↓CSF/bloodglucose
•  severeformà0.35±0.07,cutoff0.45(nv0.65);
•  mild/lateonsetformlateonset0.47-0.59(cutoff??)(Weberetal2008;Sulsetal
2008)
–  ↓lactate
•  severeformà1.1±0.35mmol/L(nv1.0-2.8mmol/L)
•  mild/lateonsetformànormal(Weberetal2008;Sulsetal2008)
•  3-O-methyl-D-glucoseuptakeintoerythrocytes
•  SLCA1geneanalysis(asfiststepforallthemild/lateonset
forms)
Ann Neurol ,
2002
A mouse model for Glut-1
haploinsufficiency
Dong Wang1, Juan M. Pascual1, Hong Yang1, Kristin Engelstad1, Xia Mao1, Jianfeng Cheng2, Jong Yoo3, Jeffrey L. Noebels3
and Darryl C. De Vivo1,*
Wang, D. et al. Hum. Mol. Genet. 2006 15:1169-1179; doi:10.1093/hmg/ddl032
Copyright restrictions may apply.
Pyridoxine/PLP dependent seizures
L-Proline
-
-
P5C
P5C-dehydrogenase
L-Lysine
P6C
AASA dehydr
AOX (MoCof)
Pyridoxic acid
(urine)
Garcia-Cazorla, Gibson, Clayton, 2012; modified
Earlyonsetmetabolicepilep$cencephalopathies
treatable
untreatable
amino-andorganicacidopathies
typicalphenylketonuria
nonketo$chyperglycinemia
serinebiosynthesisdefects
AGC1(SLC25A12)deficiency;GC1(SLC25A22)deficiency
D-2hydroxyglutaricaciduria;ethylmalonicacididuria(ETH1)
cofactordisturbances
bio$nasedeficiency
isolatedsulfideoxidasedeficiency
BH4metabolismdefects
molybdenumcofactordeficiency(typeB)
pyridoxine/pyridoxal-phosphate–dependentepilepsy(folinicacidrespSeiz)
Menkesdisease
molybdenumcofactordeficiency(typeA;MOCS1)
Cerebralfolatedeficiency(CFD):DHPR,FORL1
inbornerrorsofenerge$cmetabolism
GLUT1defect
crea$netransportdefect(males)
crea$netranspor(femalecarriers)andcrea$nesynthesis(GAMT)defects
mitochondiopathies
peroxysomaldisorders
Zellwegersyndrome,neonatalALD
lysosomaldisorders
neuronalceroidlipofuscinoses,gangliosidioses,sialidosis
disordersofneurotransmi\ers
GABAtransaminanasedeficiency
congenitaldisordersofglycosila$on
CDGIc,Ik,II
disordersofpurinemetabolism
adenylosuccinatelyasedefect
Saudubray, 2011
B6 epileptic encephalopathies/
seizures
• 
Pyridoxine dependency
• 
Pyridoxamine phosphate oxidase
• 
Hyperprolinemia type II
• 
Hypophosphatasia
• 
Drugs interfering with B6 vitamer metabolism
–  Vigabatrin
–  enzyme inducing anticonvulsivants
–  methylxantines
• 
Drugs reacting with PLP
–  Hydrazines
–  Penicillamine