From Synapse to Symptom: an overview of pediatric neurotransmitter disorders

1. From Synapse to Symptom: an overview of pediatric neurotransmitter disorders F Filloux, MD Nov 2009

2. Disclosures none

3. Pediatric Neurotransmitter Disorders??? Definition of concept Overview of CNS neurotransmitters Neuromodulation Monoamines and serotonin Excitation and inhibition: Glutamate, GABA and glycine Clinical clues

4. PNDs: Definition(s) Most pediatric neurological disorders are �neurotransmitter disorders� Term refers more specifically to: Rare inherited diseases Directly interfere with synthesis, metabolism or optimal utilization of neurotransmitters (or are postulated to do so) Affect children

5. PNDs: Disorders of monoamine metabolism GTP-cyclohydrolase deficiency (Segawa disease) Aromatic L-amino acid decarboxylase deficiency Tyrosine hydroxylase deficiency Disorders related to g-aminobutyric acid (GABA) function Pyridoxine dependency (seizure disorder) Folinic acid responsive seizure disorder Pyridoxal-phosphate dependency (PNPO deficiency) Succinic semialdehyde dehydrogenase (SSADH) deficiency GABA transaminase deficiency Disorders related to glycine metabolism Non-ketotic hyperglycinemia

6. Overview of neurotransmitters and neuro-transmission

7. Two major forms of �neurotransmission� Depend on two major types of receptors: Ionotropic Open ion channels Na+, Ca++, Cl- (change membrane polarity) Metabotropic Coupled to G-proteins (Gi, Gs, Gk) Downstream intracytoplasmic metabolic processes

8. Ionotropic vs. metabotropic effects Open/close (gate) ion channels �Fast� effects milliseconds Change postsynaptic membrane polarity depolarization or hyperpolarization �Focused� synaptic connections Glutamate, GABA, glycine, others� Act at G-protein coupled receptors �Slow� effects Seconds to minutes Affect postsynaptic metabolism cAMP , calcium mobilization, PI turnover �Diffuse� synaptic connections Monoamines, neuropeptides, others..

9. But� there is considerable overlap Glutamate/GABA act at both ionotropic and metabotropic receptors GABAA� Cl Channel; GABAB� metabotropic Metabotropic receptors may influence K-channel activity GK opens K channels? membrane stabilization

15. Simplistic correlation: Think of Monoamine disorders ? metabotropic, modulatory Movement disorders, dystonia, hypotonia, motor impairments with/without encephalopathy Amino acid neurotransmitters ? on/off, excitation inhibition Intractable seizures in early infancy

16. Monoaminergic pathways Dopamine (DA), norepinephrine (NE), serotonin (5-HT) Arise in brainstem/mesencephalon Project more or less widely to forebrain **these are neuromodulators

18. Origin of dopaminergic projections

29. PNDs 2e to Disturbances in Monomaminergic transmission GTP cyclohydrolase deficiency Segawa disease= dopa responsive dystonia= dystonia with diurnal fluctuation L-Aromatic amino acid decarboxylase deficiency (AADC deficiency) Tyrosine hydroxylase deficiency Other extremely rare conditions

30. Excitation vs. Inhibition

39. PNDs involving disturbances of amino acid neurotransmission Pyridoxine responsive seizures ALDH7A1 gene mutations (Antiquitin def) Pyridoxal phosphate responsive seizures Pyridox(am)ine phosphate oxidase (PNPO) deficiency Folinic acid responsive seizure disorder Allelic with pyridoxine responsive seizures SSADH deficiency (succinic semialdhyde dehydrogenase deficiency) Non-ketotic hyperglycinemia

40. Clinical patterns potentially warranting evaluation for PNDs Early childhood refractory epilepsies Unexplained motor impairments Particularly if early onset, diurnal fluctuation, rigidity-dystonia Unexplained global developmental delay Particularly with epilepsy, severe expressive language impairment especially if associated with autonomic dysfunction

41. Clinical conditions warranting evaluation for PNDs Early childhood refractory epilepsies Neonatal epileptic encephalopathies Early Infantile epileptic encephalopathies Suppression-burst patterns (EEG) Mixed refractory seizures early in childhood Unexplained infantile spasms Failure to respond to �standard� antiepileptics Normal or nonspecific imaging Other diagnostic studies unremarkable Infectious eval, metabolic studies, genetic studies etc�

42. Clinical conditions warranting evaluation for PNDs Motor impairments: Movement disorders: Neonates and infants: profound hypotonia, dysphagia, oculogyric crises,convergence spasms, tremor, dystonia, hypertonia, rigidity, spasmodic dystonia Older children Dystonia, (particularly with diurnal fluctuation) �cerebral palsy� (without explanation, atypical, progressive) �spastic diplegia� (as above)

43. Clinical conditions warranting evaluation for PNDs Developmental delay Particularly if unexplained after thorough evaluation plasma AAs, OAs, acyl-carnitine profile, lactate/pyruvate, MRI brain, MR spectroscopy, NH3, biotinidase activity, genetic evaluation and microarray +/- other studies With profound hypotonia With dystonia (oculogyric crises), parkinsonism, tremor, other movement disorders With severe expressive language impairment With epilepsy With autonomic aberrations

44. Conclusions PNDs rare disorders Due to impairment of neurotransmitter metabolism Monamines, glutamate, GABA, glycine Diagnosis based on clinical features, CSF analysis, genetic testing Manifestations are pleiotropic Movement disorders, developmental impairment, intractable epilepsy of very early onset May mimic more common pediatric neurologic conditions