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Metabolic Disease as a Presenta0on of Epilepsy
Dr Manju Kurian Wellcome Trust Intermediate Clinical Fellow, UCL-‐Ins=tute of Child Health Honorary Consultant in Paediatric Neurology Great Ormond Street Hospital
Overview Epilep0c encephalopathies of metabolic origin
• Spectrum of pathogenic mechanisms • Spectrum of diseases according to age • Clinical clues guiding a metabolic diagnosis • Biochemical clues • Glucose Transporter Defects • B6-‐related epilep0c encephalopathy • Treatment strategies
Defini0ons
• Inborn errors of metabolism • Present with epilepsy as a major feature in infancy
• Rare • Important to recognise • Many currently treatable • Gene0c basis for majority of IEM now elucidated • Implica0ons for gene0c/prenatal counselling
IEM in Infan0le Epilepsy
IEM and Epilepsy
Electrolyte disturbance
Hypoglycaemia Hyperammonaemia
Vitamin and cofactor
deficiencies
Cerebral energy deficiency
Disrup:on of neurotransmission
Cerebral accumula:on of abnormal storage
material
IEM and Age of Epilepsy Presenta0on NEONATAL/EARLY INFANCY LATE INFACY/EARLY CHILDHOOD
PDE, PNPO Milder PDE/PNPO
CDG CDG
Congenital NCL Infan0le/late infan0le NCL
Bio0nidase deficiency Mitochondrial including Alpers
GLUT1 Gangliosidosis/sialidosis
NKH Crea0ne synthesis defects
Serine biosynthesis disorders
MoCoF and SOX deficiency
Peroxisomal disorders
Menkes
Clinical Clues to IEM causing epilepsy • Early onset seizures – wide differen0al
• Parental consanguinity, affected sibling • Abnormal fetal movements • Seizures related to metabolic stress • Facial dysmorphia, hair, skin • Ophthalmological assessment • Mul0systemic involvement • EEG • MRI/MRS
• Seizure type?
Clinical Clues to Diagnosis (1)
• Onset 3 months • Mul0focal seizures • Evolved to infan0le spasms
• Catastrophic onset of seizures from 6 weeks • Mul0focal, myoclonic • Raised ALT • Liver failure with sodium valproate
Clinical Clues to Diagnosis (2)
Clinical Clues to Diagnosis (3) • Early onset epilepsy • Severe global developmental delay • Severe axial hypotonia • Prominent speech delay
Clinical Clues to Diagnosis (4) • 4 month old of consanguineous parents • Intractable seizures • Apnoea, intermi^ent stridor • Global hypotonia • Alopecia • Rash
Clinical Clues to Diagnosis (5)
• Normal birth • Onset of severe intractable seizures at D5 • Lethargy, encephalopathy, • EEG
Biochemical Markers of IEM
• Full neurometabolic screen • Plasma • Urine • CSF • Clues to diagnosis
• Confirmatory gene0c studies
Inves:ga:on Abnormality Inborn error of metabolism associated with infan:le epilepsy
Glucose Low FAO Glycogen storage disorders Disorders of gluconeogenesis
Ammonia High Urea cycle defect Organic acidaemias
Lactate High PDH deficiency Mitochondrial respiratory chain defects Bio0nidase deficiency
LFTs High Alpers Mitochondrial deple0on syndrome
CK High Dystroglycanopathies
Rou0ne Clinical Chemistry
Specialised Blood Inves0ga0ons Inves:ga:on Abnormality Disorder
Amino Acids High glycine High glycine/threonine Low serine High phenylalanine
NKH PNPO/PDE Serine biosynthesis Untreated PKU
Urate Low Molybdenum cofactor deficiency
Copper/caeruloplasmin Low Menkes
VLCFA High Peroxisomal
Bio0nidase Low Bio0nidase deficiency
TIEF Abnormal glycoforms CDG
White cell CoQ Low CoQ10 biosynthesis disorders Mitochondrial disorders
Vacuolated lymphocytes Present Lysosomal storage disorders NCL
Urine Metabolic Inves0ga0ons Inves:ga:on Abnormality Disorder
Organic acids Vanillactate Specific organic acids Krebs cycle intermediates
PNPO deficiency Organic acidaemias Mitochondrial defects
Sulphite High Sulphite oxidase deficency MoCoF deficiiency
Guanidinoace0c acid High GAMT
Crea0ne Low High
GAMT Crea0ne transporter deficiency
αAASA High PDE
Purine/Pyrimidines Hypoxanthine Succinyladenosine
MoCoFdeficiency Adenylosuccinate lyase deficiency
CSF Inves0ga0ons Inves:ga:on Abnormality Disorder
Glucose Low GLUT1
Lactate High Mitochondrial PDH deficiency
Amino acids High glycine Low serine High threonine/glycine
NKH Serine biosynthesis disorders PNPO/PDE
PLP Low PDE/PNPO
5-‐MTHF Low DHFR deficiency FOLR1 Kearns-‐Sayre Other mitochondrial MTHFR deficiency
Glucose Transporter Deficiency
• Originally described in 1991 • Classical presenta0on: • Early onset developmental encephalopathy • Infan0le onset seizures (<2 years 90%) • Developmental delay • Acquired microcephaly • Complex movement disorder
Atypical Phenotypes
Classical phenotype Early onset seizures Developmental delay Movement disorder
Paroxysmal exercise induced dyskinesia
Milder phenotypes Seizure onset in
childhood/adolescence Absence epilepsy
Generalised epilepsy syndromes
Milder phenotypes Mild intellectual impairment
More prominent movement disorder
Diagnosis and Treatment
• CSF glucose/plasma glucose ra0o • SLC2A1 • 3-‐O-‐methyl-‐D-‐glucose uptake in erythrocytes
• Impaired glucose transport across BBB • Ketogenic diet
Case History
• Floppy at birth • Numerous seizure types – myoclonic, mul0focal • Abnormal eye movements, grimacing, irritable • Failure of mul0ple AED • Responded to trial of pyridoxine
L-‐Lysine
Saccharopine
L-‐2-‐Aminoadipate 6-‐semialdehyde
L-‐2-‐Aminoadipate
Acetyl-‐CoA
2-‐Oxoadipate
2-‐keto-‐6-‐amino caproic acid
Δ1-‐Piperideine 2-‐carboxylic acid
Pipecolic acid
Δ1-‐Piperideine 6-‐carboxylic acid
Pyridoxine-‐dependent seizures
An0qui0n Alpha amino adipic semialdehyde dehydrogenase deficiency
L-‐Lysine
Saccharopine
L-‐2-‐Aminoadipate 6-‐semialdehyde
L-‐2-‐Aminoadipate
Acetyl-‐CoA
2-‐Oxoadipate
2-‐keto-‐6-‐amino caproic acid
Δ1-‐Piperideine 2-‐carboxylic acid
Pipecolic acid
Δ1-‐Piperideine 6-‐carboxylic acid
Pyridoxine-‐dependent seizures
An0qui0n Alpha amino adipic semialdehyde dehydrogenase deficiency
PLP
P6C inac0vates PLP
L-‐Lysine
Saccharopine
L-‐2-‐Aminoadipate 6-‐semialdehyde
L-‐2-‐Aminoadipate
Acetyl-‐CoA
2-‐Oxoadipate
2-‐keto-‐6-‐amino caproic acid
Δ1-‐Piperideine 2-‐carboxylic acid
L-‐pipecolic acid
Δ1-‐Piperideine 6-‐carboxylic acid (P6C)
N COOH H
N
O
CH3
O
O P OHOH
O
H
N
O
CH3
OH
N COOH
O P OHOH
O
+
P6C – Mw 127 PLP – Mw 247
H20
H
N
O
CH3
N COOH
O P OHOH
O
Complex B – Mw 374
Complex A – Mw 356
L-‐Lysine
Saccharopine
L-‐2-‐Aminoadipate 6-‐semialdehyde
L-‐2-‐Aminoadipate
Acetyl-‐CoA
2-‐Oxoadipate
2-‐keto-‐6-‐amino caproic acid
Δ1-‐Piperideine 2-‐carboxylic acid
Pipecolic acid
Δ1-‐Piperideine 6-‐carboxylic acid
Pyridoxine-‐dependent seizures
An0qui0n Alpha amino adipic semialdehyde dehydrogenase deficiency
Diagnosis of pyridoxine-‐dependent epilepsy
• Urine/plasma/CSF αAASA • CSF/plasma Amino acids • CSF Pipecolic acid
Pyridoxal phosphate HVA/HIAA 3-‐methoxytyrosine
• Gene0cs
Pyridoxine-‐dependent epilepsy • Trial of pyridoxine with EEG recording • Infants and atypical group
• Close monitoring • IV then maintenance • Double dose in intercurrent infec0on/fever • Annual nerve conduc0on studies
• Long term prognosis good • Speech delay, moderate learning difficul0es
Folinic Acid Responsive Seizures
• Originally thought to be a dis0nct clinical en0ty • Characteris0c peak on CSF HPLC • Some pa0ents responded to pyridoxine • AASA eleva0on, muta0ons in an0qui0n • 2 disorders biochemically and gene0cally iden0cal
Conversion of Dietary Vitamin B6 to
Intracellular Pyridoxal 5’Phosphate Co-‐Factor
Pyridoxol-‐P
Pyridoxal-‐P Intes:nal phosphatases
Pyridoxamine-‐P
Pyridoxal Pyridoxamine
Pyridoxine Diet
Absorp0on Pyridoxine
Hepa0c metabolism
Pyridoxal kinase
Blood
Cell membrane
Pyridoxal
Inside cells e.g. of brain
Membrane-‐associated phosphatases
Pyridoxal-‐P Pyridoxamine-‐P
Pyridoxal-‐P
Pyridoxal-‐P
Intes:nal phosphatases
Pyridoxal kinase Pyridoxal kinase
Pyridoxal kinase
Pyridox(am)ine phosphate oxidase (PNPO)
PNPO deficiency
• Only described in a few families • FH – miscarriages, infer0lity • Onen premature • Severe neonatal seizures • Mul0focal, myoclonic, tonic • EEG – burst suppression pa^ern
PNPO deficiency • Reduced PLP metabolites in CSF • Reduced HVA/HIAA • Muta0onal analysis of PNPO
• Responsive to pyridoxal phosphate • 10-‐30mg/kg/d • Monitor LFTs
Treatments
IEM and Treatments
• Established therapies
PDE Pyridoxine PNPO Pyridoxal phosphate Bio0nidase deficiency Bio0n GLUT1 Ketogenic diet Crea0ne disorders Crea0ne Cerebral folate deficiency Folinic acid
• Experimental treatments
Menkes Copper injec0ons NKH Benzoate/Dextromethorphan GAMT Ornithine supplementa0on PDE Lysine restric0on
• Gene therapy
IEM and Treatments
Conclusion
• IEM are a rela0vely rare cause of EIEE
• Diagnosis is made on clinical grounds
• Suppor0ve biomarkers in metabolic tes0ng
• Diagnosis important
• Therapeu0c op0ons
• Prompt treatment may affect long term outcome
