Embed Size (px)
Citation preview
Treatable metabolic neonatal and infant onset encephalopathies
Allan M Lund Centre for Inherited Metabolic Diseases
Copenhagen University Hospital
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
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
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)
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
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
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
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)
One important statement about IEM diagnosis and treatment
! EARLY TREATMENT!
MSUD. Kaplan, 1991, Morton 2002 (Mennonite community, Pennsylvania)
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
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
Urin-‐metabolic screening Gas chromatography of urine
MMA
Acute intoxication IEM, like: Amino/organo acidopathies Urea Cycle Disorders
Urea Cycle IN
OUT
Acute intoxication, like: Amino/organo acidopathies Urea Cycle Disorders
Hyperammonaemia Glutamin (HPLC af Urin)
Plasma amino acids: High Glutamine Low arginine + specific changes: eg high citrulline in ASS
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
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
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
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)
Early treatment is very important
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
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
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;
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
Vitamin B6 metabolism
Vitamin B6 metabolism – PLP deficiency
AnCquiCn Deficiency, PDE
PNPO Deficiency
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
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
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
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
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
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?
AnCquiCn Deficiency – lysine restricCon
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)
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)
Folinic acid-‐responsive seizures
• = AnCquiCn deficiency
• Some report beXer effect of combined treatment, but this is uncertain
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)
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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 – ……
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!
