treatable(metabolic(neonatal(and( infantonset...
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Treatable metabolic neonatal and infant onset encephalopathies
Allan M Lund Centre for Inherited Metabolic Diseases
Copenhagen University Hospital
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Treatable metabolic neonatal and infant onset encephalopathies
• Emphasis on metabolic, treatable and epilep.c encephalopathies
• Overall frequencies, eCologies, seizure/EEG characterisCcs and age at presentaCon
• More in-‐depth descripCon of top 10 treatable IEM disorders you do not want to miss
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Neonatal, infant-‐onset epilepCc encephalopathies -‐ frequency
• Overall 1:1000 live births – Hypoxic-‐ischaemic encephalopathy (HIE)
• Most common at 50-‐60 %
– Metabolic -‐ Inborn errors of Metabolism (IEM) • Minor percentage at ≈ 3-‐5%
– But an important part is treatable
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Biochemical mechanisms of disease in IEMs
Ain B C
D
Aout 1 2
Membrane
Substrate accumulation 1)Acute intoxication
- acidosis - hyperammonaemia - energy deficiency - hypoglycaemia
2) Slowly progressive accumulation
Product deficiency Mental retardation Failure to thrive Skin and hair manifes- tations
Causes All inherited DefecCve transporter (1) DefecCve (apo)enzyme (2) DefecCve co-‐factor (2)
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Triggers of disease IEMs have many consequences and metabolic epilepCc
encephalopathies have many pathogeneCc ways • Hypoglycemia
• FatoxidaCon, GSD • Hyperammonemia
• UCD, OA • Electrolyte disturbances
• hypocalcemia
• Neurotoxicity from intermediates
• Leucine, phenylalanine • NeurotransmiXer deficiencies • Dependency of vitamins and
cofactors • Pyridoxine, bioCn, folate
• Cerebral energy deficiency • GLUT1, CreaCne,
SYSTEMIC SIGNS NONE/LIMITED SYSTEMIC SIGNS
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Some differenCal diagnoses, including
• Brain malformaCons • CAVE an IEM may cause it as well
» Mitochondrial, PDH, CDG
• Hypoxic-‐ischaemic encephalopathy (HIE) • CAVE an IEM could be the trigger and could be treatable
• Hemorrhages, infarcCon • CAVE IEM like homocysCnurias, mitochondrial disorders, may be causes as well
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Age at presentaCon of childhood epilepCc encephalopathies in general
• Newborn and infan.le onset – PDE, PNPO, MOCOD, amino/organo-‐acidopathies, hyperammonemias, bio.nidase, GLUT1, CREA, Serine deficiency,
– peroxisomal, CDG, NCL1, NKH, Mitochondriopathies, Menkes, Sialidosis
• 1-‐5 years – FOLR1, GLUT1, Alpers, NCL2, peroxisomal, LSDs
• Schoolage – NCL3, Alpers, mitochondriopathies, LSDs
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Treatable neonatal/infanCle metabolic encephalopathies
-‐ groups of disorders • Acute intoxicaCon type IEM
– Amino/organo-‐acidopathies • MMA, PA, MSUD, GA1, HCU
– Urea Cycle disorders • OTC, CPS
• Cofactor and vitamin disturbances • Pyridoxine, folic acid, bioCne, BH4, thiamine
• NeurotransmiXer deficiencies • Cerebral energy deficiencies
• CreaCne synthesis, GLUT1 • ”Metabolic” Channelopathies
• DEND (Developmental delay, Epilepsy and Neonatal Diabetes) • HIHA (HyperInsulinism-‐HyperAmmonemia)
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One important statement about IEM diagnosis and treatment
! EARLY TREATMENT!
MSUD. Kaplan, 1991, Morton 2002 (Mennonite community, Pennsylvania)
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Substrate Reduce storage: Dietetic restriction Increased elimination Alternative metabolism: alternative paths metabolic inhibitors substrate reduction
Product Replace product by: Dietetics Medical
Phenotype Symptomatic treatment Prenatal diagnosis
Enzyme Increase enzyme activity by: Vitamins Enzyme substitution Enzyme stabilisation Transplantation Gene terapy
IEM TREATMENT
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Organic acidurias
• Boy born to consanguinous parents, well from birth until day 2
• Then acutely ill • Limited sucking, vomiting, tachypnoic • Encephalopathic and later coma • Truncal hypotonia, dehydration • BE: -15, St.bicarb.: 13, pH: 7.21, glucose: 1.2 • severe U-ketosis • Typical neonatal presentation of an organic
aciduria like MMA, PA, IVA, 3-MCC
Acute intoxication, like: Amino/organo acidopathies Urea Cycle Disorders
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Urin-‐metabolic screening Gas chromatography of urine
MMA
Acute intoxication IEM, like: Amino/organo acidopathies Urea Cycle Disorders
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Urea Cycle IN
OUT
Acute intoxication, like: Amino/organo acidopathies Urea Cycle Disorders
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Hyperammonaemia Glutamin (HPLC af Urin)
Plasma amino acids: High Glutamine Low arginine + specific changes: eg high citrulline in ASS
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Hyperammonaemia • Girl born healthy • Fine at day 2 • 3 days postpartum:
encephalopatic, seizures, hypertonia, no sucking, vomiting,
• Suspected GI problem: laparotomi: ia
• Postop: coma, non-reacting pupils
• Ammonia >2935 (umålelig høj) – Haemodialysis – Sodium penylbutyrate – Arginine – Carbaglu
• 12t: 956 • 24t: 249 • 36t: 93 • Normal siden
– Stopped haemodialysis after 24 hours
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Hyperammonaemia • Next day
• Protein added • Essential+branched chain • Phenylbutyrate+arginin
• Following days: • EEG normal • Better muscular tonus • Good contact
• Freja was well first five years • Initial slow weight gain • Good contact, development
• Death at five years – gastroenteritis • Hyperammonaemia with cerebral
incarceration and death
• Urine + P-amino acids: • High citrullin+ alanin • Low Arginin
• CITRULLINEMIA
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Urea Cycle disorders may be eminently treatable
Always measure AMMONIA early and if in doubt, in cases of unclear sepCcaemia, seizures, encephalopathy
May be a difficult diagnosis with limited systemic signs
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Hyperammonaemia does not always mean urea cycle disorder
• Inherited – Organic acidaemias – Fat oxidaCon defects – Pyruvate carboxylase D – HHH – LPI – Carbon anhydrase D – HIHA
• Other – Severe neonatal disease
• Max 200 µmol/l – Asphyxia – Leverinsufficiency – THAN (Transient hyperammonaemia)
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Early treatment is very important
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Principles of acute treatment Intoxication type IEM, like UCD, OA, MSUD
• Stop normal feeding, give 10% glukose iv • 8-10 mg/kg/min • 80-100 kcal/kg/d
• + lipid
• Correction of dehydration/acidosis • Treat seizures; avoid valproic acid • Medicines depending on suspected condition
• Carnitine, vitamins, ammonia scavengers, dialysis • If UCD is suspected:
• NH3 200-400 µmol/l • MEDICAL THERAPY
• NH3 > 400 µmol/l • DIALYSIS + MEDICAL THERAPY
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Principles of treatment in UCD
Medical therapy • 1. Increase N-excretion
– Sodiumbenzoate – Sodiumphenylbutyrate
• 250 mg/kg as bolus and daily • 2. Catalyse urea cycle
– Arginine • 600 mg/kg/day
• 3. Activate CPS – Carbaglu
• 200 mg/kg/day
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Co-‐factor and vitamin disturbances
• Transport defects • bioCn-‐thiamine BGD, folate receptor defects
• Enzyme-‐KM-‐variants • B6 responsive homocysCnuria , B12 responsive MMA
• Co-‐factor/vitamin synthesis and recyling disturbances
• BioCnidase, PNPO, BH4, hypophoshatasia • Co-‐factor/vitamin inacCvaCon
• AnCquiCn deficiency (PDE), hyperprolinemia
• NuCConal deficiencies • NutriConal B12 deficiency;
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Vitamin B6 dependent epilepsies/encephalopathies
• Disorders with reduced availability of Pyridoxal-‐5-‐Phosphate (PLP) • PLP is the acCve metabolite of vitamin B6 • A co-‐factor for >140 different enzymes (esp. in amino acid and
neurotransmiXer metabolism)
• Two groups – InacCvaCon of PLP
• An8qui8n deficiency (PDE) • Hyperprolinemia type II
– Impaired formaCon and cellular uptake of PLP • PNPO deficiency • Congenital hypophosphatasia • Hyperphosphatasia with Mabry syndrome
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Vitamin B6 metabolism
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Vitamin B6 metabolism – PLP deficiency
AnCquiCn Deficiency, PDE
PNPO Deficiency
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PLP deficiency
• Large clinical overlap for anCquiCn and PNPO – Neonatal onset, therapy resistent seizures
• Response to pyridoxin in AnCquiCn D and to Pyridoxal-‐5-‐phosphate in PNPO D
• AddiConal clinical features for the other 3 disorders
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Clinical features AnCquiCn deficiency, PDE
• Early presentaCon of seizure, someCmes in utero – 90% onset within first 28 days postpartum, some later and up to age 3 years
• Prolonged seizures, recurrent status • Many types, incl mulCfocal, generalised myoclonia
– And signs of encephalopathy with irritability, grimacing, tonic symptoms, orofacial dystonia, abnormal eye movements …
• Therapy resistent • Total in 60%, parCal in rest
• Poor general condiCon, prematurity, fetal distress, low apgars, hypotonia, feed intolerance – May mimic HIE or sepsis
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Clinical features -‐ PNPO • Early presentaCon within first 28 days postpartum
– A few later in infancy (up to 5 months) • Abnormal intrauterine movements • Prolonged seizures, recurrent status • Many, including mulCfocal, generalised myoclonia
– And irritability, grimacing, tonic symptoms, orofacial dystonia, abnormal eye movements
– West syndrome (-‐ broadening the phenotype)
• Therapy resistent in 80% • EEG with burst suppresssion and hypsarrhythmia • Prematurity, fetal distress, low apgar scores, hypotonia,
repiratory distress • FerClity issues in carriers
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AnCquiCn and PNPO deficiency Diagnosis – pyridoxine/PLP trial
• Intensive care unit – Severe hypotonia, apnoea, resp. decompensaCon in 25%
• Save plasma, urine and CSF • Give Pyridoxine 100 mg iv during EEG recording followed by 30 mg/
kg/day orally in 2-‐3 SD – Clinical effect within minutes to 1 hour; EEG may change later – IV dose could be replaced by oral treatment -‐ wait at least 5 days to
exclude a response • If ineffecCve repeat up to a maximum of 500 mg • If ineffecCve, add folinic acid 3-‐5 mg/kg/day, 1-‐2 SD, po • If ineffecCve give PLP 30-‐60 mg/kg/day in 4-‐6 SD, po • No withdrawal if effecCve at any point
– If seizures stop, conCnue pyridoxin or PLP unCl biochemical/molecular results are available
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AnCquiCn and PNPO deficiency Pyridoxine/PLP trial – comments and pilalls
• Full response in most • 90% in AnCquiCn Deficiency
• Quick response • 90% immediate response in AnCquiCn • 80% within 3 days in PNPO • However in few: no response neonatally but only later -‐ aner months
• Some with PNPO have a full response to pyridoxine • Certain mutaCons, riboflavine binding site, prematurity
• Some iniCally respond to convenConal drugs and become intractable later with a posiCve vitamin response at that point
• Some remain seizure free for extended periods despite withdrawal • PLP will work as good as pyridoxine as the iniCal agent in the trial,
but pyridoxine most onen used as the iniCal drug • PLP hepatotoxicity (possible) • Higher frequency of anCquiCn deficiency • PLP is unlicensed and not broadly available
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AnCquiCn deficiency Long-‐term treatment
• Pyridoxine 15-‐30 mg/kg/day, lifelong – Minimal effecCve dose – Look for peripheral neuropathy
• Max 200 mg in children and 500 mg in adults – Double dose during intercurrent illness unCl child is well
• Most will be seizure free on Pyridoxine, however – 20% need addiConal anCepilepCc drugs – 80 % has mild-‐moderate developmental delay, auCsm – WM abnormaliCes and NAA reducCon on MRS
• Intermediates from disturbed lysine degrada8on remains elevated despite pyridoxine
– Could a lysine restricted diet be helpful?
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AnCquiCn Deficiency – lysine restricCon
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AnCquiCn deficiency Dietary lysine restricCon
• Well tolerated • Decreases neurotoxic biomarkers • PotenCal benefit for seizure control and neurodevelopmental outcome
• Ongoing invesCgaCons – refer paCents
• (L-‐arginine supplementaCon)
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PNPO deficiency Longterm treatment
• Pyridoxal-‐5-‐phosphate, 10-‐60 mg/kg/day in 4-‐6 SD • More sensiCve to regular drug intervals than PDE • Doubling of dose during intercurrent illness
• Higher rate of break-‐through seizures than in anCquiCn D • Regular liver US and biochemical invesCgaCons • Speech and motor delay in at least half
• For both PNPO and AnCquiCn – Treatment in subsequent pregnancies (last trimester)
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Folinic acid-‐responsive seizures
• = AnCquiCn deficiency
• Some report beXer effect of combined treatment, but this is uncertain
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Biomarkers Urine Plasma CSF B6 response
PNPO Vanillactate ↓PLP ↑Thr/gly; ↓Arg
↓PLP ↓HVA/5HIAA ↑Thr/gly(/his/tau)
PLP (pyridoxine in some)
AnCquiCn AASA, P6C ↑Pipecolic acid (AASA) ↑Thr/gly
↓PLP ↓HVA/5HIAA ↑Thr/gly ↑AASA
Pyridoxine or PLP
Hypophosphatasia ↓AP ↓Ph ↑Ca
Pyridoxine or PLP
Hyperprolinemia ↑Proline, P5C ↑Prolin, P5C ↑Prolin, P5C Pyridoxine or PLP
Gene tes8ng AnCquiCn Confirmatory ALDH7A1 sequencing; p.Glu399Gln in 30% of alleles PNPO No good biomarkers –low threshold for PNPO sequencing
AASA = alpha-‐aminoadipic semialdehyde P6C = L-‐∆1Piperideine-‐6-‐carboxylate P5C = L-‐D1-‐pyrroline-‐5-‐carboxylate (RED = (almost)patognomic)
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Who to invesCgate?
• The child with classical presentaCon • Those parCally responsive to anCepilepCc drugs when it is combined with psychomotor delay
• Neonates with HIE and difficult to control seizures
• Those with a history of a response to folinic acid or only transient response to pyridoxine
• Difficult seizures in any child < age 1 year without an apparent cause of epilepsy
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The other diseases with reduced PLP availability and some effect of
Pyridoxine and PLP • Hyperprolinemia type II
• Later onset seizures (infancy to childhood) • Some with MR
• Congenital Hypophosphatasia • Neonatal therapy resistant seizures; skeletal manifestaCons, but seizures may occur before
• Fatal in most with early presentaCon • BeXer outcome with later presentaCon
– ERT with subcutaneous recombinant alkaline phosphatase is now available
• Mabry syndrome • Early seizures, MR, hypotonia, facial dysmorphia, hypoplasCc terminal phalanges
• Hyperphosphatasia
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BioCn-‐thiamine responsive basal ganglia disease
• Neonatal acute encephalopathy with epilepsy and Leigh syndrome in few
• InfanCle spasms in some
• PresentaCon aner age 3 in most
• BioCn/thiamine trial
• SLC19A3 sequencing
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BioCn MulCple Carboxylase deficiency
BioCnidase/holocarboxylase synthase deficiency • Neonatal/infanCle
presentaCon • Seizures (infanCle spasms),
encephalopathy, hypotonia • Developmental delay • Eczema, alopecia • Hearing loss • Organic aciduria, lacCc
acidosis, metabolic acidosis • All respond to bioCn, 5-‐10 mg • Neonatal screening
– HLCSD common in the Faroes
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Cerebral Folate Deficiency • Reduced CSF-‐5MTHF
• Mostly caused by FOLR1 anCbodies or secondary to other IEM (such as MTHFR) or other diseases like ReX
• Folate receptor 1 defects (infanCle)
• Irritability, seizures • Movement disorder • Microcephaly, hypomyelinaCon,
basal ganglia calcificaCons, DD
• Dihydrofolate reductase deficiency
• InfanCle onset • Microcephaly, epilepsy, brain
atrophy • Pancytopenia
• Some effect of folinic acid 3-‐5 mg/kg/day
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Disorders of tetrahydrobiopterin (BH4) metabolism
BH4 dependent pathways
Deficiency of monoamine neurotransmiXers, including dopamine and serotonine Some with elevetad phenylalanine and picked up by neonatal screening
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Disorders of tetrahydrobiopterin (BH4) metabolism
• Most common epilepCc enCCes: PTPS or DHPR • CombinaCons of epilepsy, movement disorders and symtoms from the autonomous nervous system – Myoclon epilepsy – Dystonia, dyskinesia, hypokinesia, chorea, rigidity – Miosis, ptosis – Developmental delay
• SubsCtuCon with L-‐DOPA, 5-‐hydroxytryptophan, folinic acid and BH4; PKU-‐diet in some
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Cerebral energy deficiency -‐ GLUT1 deficiency
• DefecCve transport of glucose into brain – CSF glucose < 2mM – CSF/blood raCo of glucose < 0.5 – FasCng (4 h), non-‐stressed – Some false negaCves
• Molecular-‐gene.c analyses of ALC2A1 is now gold standard
– De novo heterozygous mutaCons in most
• Huge variaCon in clinical presentaCon • Some present in 1st year of life (classical)
– Epilepsy – most common presentaCon (90%) • 80% wiCn first 6 months of life • CyanoCc aXacks, opsoclonus-‐myoclonus,
abscences • Therapy resistant
– Valproat and phenobarbital may worse
– Microcephaly, developmental delay, paroxysmal movement disorder, ataxia, dysarthria
• Later presentaCons include – Dystonia, absence epilepsy, intermiXent
ataxia, alternaCng hemiplegia
• KETOGENIC DIET – Go for relaCvely high ketone levels
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Cerebral energy deficiency
CreaCne deficiency • DefecCve creaCne biosynthesis
– GAMT, AGAT
• DefecCve transport – CT1 (SLC6A8,X-‐linked)
• Diagnosis – low MRS cerebral creaCne – P+U guanidinoacetate, creaCne and creaCnine
– Sequencing
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Cerebral energy deficiency CreaCne deficiency
• Epilepsy (> 90% of paCents), mulCple types • Hypotonia, delayed psychomotor development, speech delay
• Treatment: – CreaCne in all – GAMT – reduce guanidinoacetate
• arginine restricCon • ornithine supplementaCon
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Other treatable IEM epilepCc encephalopathies?
• Serine biosynthesis defects • Low CSF-‐serine (and glycine) • Early microcephaly, infanCle spasms • Some effect of early serine supplementaCon
• Deficiency of molybdenum cofactor (defecCve xanthine DH, sulphite oxidase and aldehyde oxidase) and isolated sulphite oxidase
• Early epilepsy, dystonia and DD • Diagnosis with U-‐sulphite test (and abnormal purines and low urate in molybdenum
cofactor deficiency) • MOCOD paCents with a block of GTP to cyclic pyranopterin may benefit form
supplemtaCon of cyclic pyranopterin
• Non-‐ketoCc hyperglycinaemia • Almosdt always untreatable; sodium benzoate and dextromethorphan may help mild
cases • Menkes disease
• Copper hisCdine – limited effect
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Approach to diagnosis Common characterisCcs?
• Some may have had intrauterine seizures with abnormal intrauterine movements • Most are well at birth and present aner asymptomaCc phase (hours to weeks) • Systemic disease, acid-‐base disturbances, incl lacCc acidosis, liver dysfuncCon may
be present • Failure to thrive, poor feeding, hypotonia, encephalopathy • InfanCle spasms and myoclonic encephalopathy/seizures • Abnormal background acCvity, hypsarrhytmia, burst suppression • Poor or no response to tradiConal anCepilepCcs • Consanquinity, previous cases in sibship • Few other clinical signs, including
– Skin/hair abnormaliCes • BioCnidase, holocarboxylase
– Micro-‐macrocephaly
• Above are points to increase awareness – However, isolated encephalopathy and intractable seizures without an obvious cause or
systemic abnormality are equally important
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Neonatal metabolic encephalopathy without hypoxia, dysmorphia, macrocephaly, organomegaly, acid-‐base disturbances, hypoglycemia
etc ….
• That is a ”Non-‐hypoxic phenotype resembling hypoxic-‐ischemic encephalopathy”
– most common metabolic causes • Non ketoCc hyperglycemia • Sulphite oxidase deficiency • Pyridoxine/PLP dependency • GLUT 1 deficiency • CreaCne deficiency • Serine biosynthesis disorders
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Approach to diagnosis • Overall few clinical hints in neonatal/early infant presentaCons – Most clinical symptoms are unspecific, e.g.
• Hiccups, vomiCng, feeding problems, hypotonia, hypertonia, cycling movements, encephalopathy etc
• Diagnosis depends in many cases on screening • Selected diagnosCc invesCgaCons: EEG, MRI, MRS • Biochemical invesCgaCons
– Neonatal screening – SelecCve metabolic screening
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Approach to diagnosis -‐ SelecCve screening
• Urine metabolic screening – Organic acids, aminoacids, purine/pyrimidines, sulphite, reducing substances, creaCn/
creaCnine, guanidinoacetate, ketones – Save urine
• Blood analyses – RouCne: Glucose, ammonia, lactate, urate, S/B-‐balance, anion-‐gap, creaCne,
creaCnekinase, LFT – Special: AcylcarniCnes, aminoacids, purines/pyrimidines – Save plasma
• CSF – Lactate, aminoacids, CSF/B-‐glucose raCo, CSF/B-‐glycine raCo, neurotransmiXers – Save CSF
• Enzymes – BioCnidase, GCDH
• DNA – As a confirmaCon, for geneCc counselling and prenatal diagnosis – In the future: as a screening instrument e.g. in panels for epilepCc encephalopathies
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Remember – the clock is always Ccking for the child with treatable IEMs
• Graph is for Hyperammonemia • ….. but principle is the same for
many, like
– MSUD – Pyridoxine dependency – BH4 deficiencies – GLUT1 – BioCnidase – ……
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Top 10 IEMs you cannot afford to miss?
• Acute intoxicaCon IEMs, including hyperammonemia • PLP Dependency • BioCnidase/HLCSD • BH4 defects – atypical PKU • GLUT1 deficiency • CreaCne deficiency • BioCne-‐thiamine BGD • Cerebral Folate Deficiency • Serine biosynthesis Deficiency • RemethylaCon Deficiency
• ….. and add your own ones …
THANK YOU!