Neurotransmitter Disorders
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University Children’s Hospital Zürich, Switzerland Neurotransmitter Disorders Clinical Presentation and Diagnosis Nenad Blau ERNDIM Meeting, 22-23 October 2009 – Basel - CH University Children’s Hospital Zürich, Switzerland Definition Neurotransmitters are chemicals (biogenic amines, amino acids, purines, neuropeptides, etc.) that are released from neurons and that change the electrical activity of other neurons or of myocytes. University Children’s Hospital Zürich, Switzerland Classification •Disorders of tetrahydrobiopterin (BH4) •Disorders in catecholamines and serotonin metabolism •Disorders of serine and glycine metabolism •Disorders of glutamate and GABA •Disorders of folate deficiency •Disorder of B6 metabolism University Children’s Hospital Zürich, Switzerland Classification •Disorders of tetrahydrobiopterin (BH4) • with hyperphenylalaninemia • GTP cyclohydrolase I (ar) • 6-Pyruvoyl-tetrahydropterin synthase • Dihydropteridine reductase • without hyperphenylalaninemia • GTP cyclohydrolase I (ad) - University Children’s Hospital Zürich, Switzerland Tetrahydrobiopterin Metabolism Guanosin Triphosphate (GTP) GTPCH Dihydroneopterin Triphosphat PTPS 6-Pyruvoyltetrayhdropterin SR Tetrahydrobiopterin (BH4) Phenylalanin Tyrosine e PAH DHPR TH Tryptophan TPH PCD qDihydrobiopterin Pterin-4acabinolamin Tyrosin e L-Dopa 5-OH-Tryphtophan University Children’s Hospital Zürich, Switzerland Classification •Disorders in catecholamines and serotonin metabolism • Tyrosine hydroxylase • Aromatic amino acid decarboxylase • Monoamine A oxidase •Dopamine-β-hydroxylase University Children’s Hospital Zürich, Switzerland Disorders in catecholamines and serotonin metabolism University Children’s Hospital Zürich, Switzerland Classification •Disorders of serine and glycine metabolism • 3-Phosphoglyceratedehydrogenase • 3-Phosphoserine phosphatase • Phosphoserine aminotransferase • Glycine cleavage system University Children’s Hospital Zürich, Switzerland Disorders of glycine and serine metabolism FR H MT CO2 + NH4+ NADH 5,10-MTHF 5-CH3-THF Glycine Glycine Cleavage System PLP Ser-Hydroxymethyltransferase Glycine NAD+ THF Serine 3-Phosphoserine phosphatase P-Serine Phosphoserine aminotransferase 3-P-Hydroxypyruvate 3-Phosphoglyceratedehydrogenase Glucose 3-P-Glycerate Lactate University Children’s Hospital Zürich, Switzerland Classification •Disorders of glutamate and GABA • Succinate semialdehyde dehydrogenase • γ-Aminobutyric acid transaminase • Glutamine synthase University Children’s Hospital Zürich, Switzerland Disorders of glutamate and GABA Neuron Glutamate Astrocyte Glutamine Glutaminase Glutamine synthase GABA γ-Aminobutyric acid transaminase SSA Succinate semialdehyde dehydrogenase Succinate TCA cycle Glutamate University Children’s Hospital Zürich, Switzerland Classification •Disorders of folate deficiency • Hereditary folate malabsorption • Methylentetrahydrofolate reductase • Folate receptor alpha • Cerebral folate deficiency University Children’s Hospital Zürich, Switzerland Disorders of folate transport University Children’s Hospital Zürich, Switzerland Disorders of folate metabolism B12 ATP Ser 3Pi THF Met Gly 5,10-Methylene-THF SAM MS NADH + H+ SAH Methylentetrahydrofolate reductase NAD+ 5-CH3-THF Homocysteine Adenosine Methyl-B12 H2O University Children’s Hospital Zürich, Switzerland Classification •Disorders of B6 metabolism • α-Aminoadipicsemialdehyde DH • Pyridoxamine-5’-phosphate oxidase University Children’s Hospital Zürich, Switzerland Disorders of B6 metabolism Lysine Pyridoxine (B6) Pipecolic acid Pyridoxalphosphate (PLP) α-Aminoadipicsemialdehyde α-Aminoadipic acid Δ-Piperidein-6caboxylate University Children’s Hospital Zürich, Switzerland Secondary Biogenic Amine Deficiencies Primary • Defects in biosynthesis (non- Secondary • Classical PKU HPA) Enzyme deficiencies GTP cyclohydrolase I Tyrosine hydroxylase Tryptophan hydroxylase Aromatic amino acid decarboxylase Dopamine β-hydroxylase Cofactor (BH4) deficiency (HPA) • Defect in catabolism Monoamine oxydase A Competitive inhibition of TH and TPH • Lesch-Nyhan syndrome • Rett syndrome • Arginase deficiency • Menkes disease • Viral infections • Familial erythrophagocytic lymphohistiocytosis University Children’s Hospital Zürich, Switzerland Guidelines for the Screening Newborn Newborn screening screening normal normal ‘Missed’ ‘Missed’ cases cases No NoHPA HPA or or not tested not tested ‘Undiagnosed ‘Undiagnosed neurological neurological disease’ disease’ Central Centraland/or and/orperipheral peripheralnervous nervoussystem system dysfunction with either/and/or: dysfunction with either/and/or: Typical Typical ••Hypokinesia Hypokinesia ••Distal Distalchorea chorea ••Myoclonic Myoclonicepilepsy epilepsy ••Temperature Temperaturedisturbance disturbance ••Hypersalivation Hypersalivation Non -specific Non-specific ••Mental Mentalretardation retardation ••Microcephaly Microcephaly ••Developmental Developmentaldelay delay ••Pinpoint pupils Pinpoint pupils ••Irritability Irritability ••Convulsions Convulsions ••Oculogyric Oculogyriccrises crises ••Hyperor hypotonia Hyper- or hypotonia ••Swallowing Swallowingdifficulties difficulties ••Dystonia (diurnal Dystonia (diurnalvariations) variations) Biogenic Biogenicamine amine and metabolite and metabolite analysis analysis (P, (P,CSF CSFor orU) U) University Children’s Hospital Zürich, Switzerland SIGNS & SYMPTOMS + TREATMENT Patients‘ pictures and movies removed from the presentation University Children’s Hospital Zürich, Switzerland Symptoms Related to Specific Biogenic Amine Deficiency Dopamine Serotonin Norepinehrine Immobility Depression Axial hypotonia Parkinsonism Altered thermogenesis Cerebellar symptoms Sleepiness Insomnia Ptosis Dystonia Eye rolling Hypersalivation Swallowing difficulties University Children’s Hospital Zürich, Switzerland Dopa-responsive Dystonia (DRD) Dopa-responsive Dystonia (DRD) - GTP Cyclohydrolase I Deficiency Inheritance autosomal dominat (14q22.1-q22.2 ) E2X L79P E65X R88W R88P M102K Q110X S114X exon 1 D115N D134V C141W >15kb H153P Q182X R184H I171X G201E R178S G203R M211I R216X K224R K224X F234S 5.6kb 9kb 1.2kb 1.4kb exon 2 exon 3 exon 4 exon 5 ATG 100 bp exon 6 TAG IVS1G-1A IVS1A-2G IVS2G+1C IVS2A-2G Signs & Symptoms Onset : neonatal Onset: neonatal--adolescence adolescence Dystonia Dystonia Diurnal Diurnalvariation variationof ofsymptoms symptoms Parkinsonism Parkinsonism Spasticity Spasticity Hyperreflexia Hyperreflexia Rigidity Rigidity Pyramidal Pyramidalsigns signs red = hyperphenylalaninemia blue = Dopa-responsive dystonia Diagnosis CSF: CSF:HVA HVAÐ Ð;;5HIAA 5HIAAnn--Ð Ð;;Neo Neo& &Bio BioÐ Ð Oral Oral::Phe Phe(100 (100mg/kg); mg/kg); L-Dopa/Carbidopa L-Dopa/Carbidopa Treatment L-Dopa/Carbidopa L-Dopa/Carbidopa (2-5 (2-5mg/kg/d) mg/kg/d) University Children’s Hospital Zürich, Switzerland Disorders Catecholamines Therapy: L-dopa/Carbidopa University Children’s Hospital Zürich, Switzerland Disorders of Serotonin and the Catecholamines University Children’s Hospital Zürich, Switzerland Most common signs and symptoms in patients with AADC deficiency Diagnosis, outcome, and long-term follow-up of 78 patients with aromatic L-amino acid decarboxylase deficiency: Lesson from the international database of pediatric neurotransmitter disorders. Brun L et al. (2009) Neurology, submitted University Children’s Hospital Zürich, Switzerland Most frequently used medications in patients with AADC deficiency. University Children’s Hospital Zürich, Switzerland Databases of Pediatric Neurotransmitter Disorders www.BIOPKU.org University Children’s Hospital Zürich, Switzerland Databases of Pediatric Neurotransmitter Disorders www.BIOPKU.org University Children’s Hospital Zürich, Switzerland Databases of Pediatric Neurotransmitter Disorders www.BIOPKU.org University Children’s Hospital Zürich, Switzerland Databases of Pediatric Neurotransmitter Disorders www.BIOPKU.org University Children’s Hospital Zürich, Switzerland Conclusions Patients with typical signs and symptoms of psychomotor retardation with hypo/dyskinesia, truncal hypotonia, ataxia, oculogyric crises and epileptic seizures should be tested for CSF neurotransmitter metabolites, amino acids and folates. Children’s Hospital Zürich (1995 – 2009) 5’100 CSF samples 5-6% pathological profile 1.8% with final diagnosis
