From  Synapse to Symptom:  an overview of pediatric neurotransmitter disorders F Filloux, MD Nov 2009
Disclosures <ul><li>none </li></ul>
Pediatric Neurotransmitter Disorders??? <ul><li>Definition of concept </li></ul><ul><li>Overview of CNS neurotransmitters ...
PNDs:  Definition(s) <ul><li>Most pediatric neurological disorders are “neurotransmitter disorders” </li></ul><ul><li>Term...
PNDs:  <ul><li>Disorders of monoamine metabolism </li></ul><ul><ul><li>GTP-cyclohydrolase deficiency (Segawa disease) </li...
<ul><li>Overview of neurotransmitters and neuro-transmission </li></ul>
Two major forms of “neurotransmission” <ul><li>Depend on two major types of receptors: </li></ul><ul><li>Ionotropic </li><...
Ionotropic  vs.   metabotropic  effects <ul><li>Open/close (gate) ion channels </li></ul><ul><li>“ Fast” effects </li></ul...
But… there is considerable overlap <ul><li>Glutamate/GABA act at both ionotropic and metabotropic receptors </li></ul><ul>...
From Kandel, Schwartz, Jessell, Principles of Neural Science, 2000.
 
Diagram of typical metabotropic receptor.  Note 7 transmembrane domains; intracytoplasmic loop between 5-6 th  lC domains ...
Schematic of G-protein: Activation of metabotropic receptor results in phosphorylation of GDP on alpha subunit.  Activated...
Schematic of metabotropic receptor. Binding of agonist (glutamate) results in phosphorylation of the G-protein and resulta...
Simplistic correlation: <ul><li>Think of </li></ul><ul><li>Monoamine disorders    metabotropic, modulatory </li></ul><ul>...
Monoaminergic pathways <ul><li>Dopamine (DA), norepinephrine (NE), serotonin (5-HT) </li></ul><ul><li>Arise in brainstem/m...
http://content.answers.com/main/content/img/oxford/Oxford_Mind/0198162246.parkinsons-disease.2.jpg Dopaminergic pathways o...
Origin of dopaminergic projections Normal Parkinson  Disease Adapted from:  http://www.mdvu.org/images/par_path1.jpg
Axial brain sections at level of rostral substantia nigra and basal ganglia.
Coronal brain sections at level of Caudate, putamen and globus pallidus.  Plate B includes subthalamic nucleus (STN) and r...
Immunofluorescence of a DA cell from the VTA.  Note the distal process and long ramification.  DA is often released from a...
Influence of dopamine (DA) on output of the caudate/putamen.  Open arrows, excitatory; black arrows, inhibitory.  Net effe...
Noradrenergic pathways of human brain.  Primary origin of forebrain NE is from the locus ceruleus in the dorsal pons. http...
Locus ceruleus Origin of forebrain noradrenergic projection
Serotonin pathways in human brain … http://www.wellspringchiro.com/ws3_serotonin.jpg
Catecholamine synthesis: Rate limiting step is first step, tyrosine hydroxylase.  Tetrahydrobiopterin is co-factor for TH.
 
HVA  HIAA MHPG Tyr  Trp   Phe 3-OMD Monoamine Synthesis Adapted from Hyland, Swoboda and others GTP Cyclohydrolase Neopterin
PNDs 2 e  to Disturbances in Monomaminergic transmission <ul><li>GTP cyclohydrolase deficiency </li></ul><ul><ul><li>Segaw...
Excitation vs. Inhibition N- CH- CH2- CH2- COOH N- CH- CH2- CH2- COOH COOH H H H H Glutamic Acid GABA Glutamic acid decarb...
Pyridoxal-5- phosphate
PNPO = pyridox(am)ine oxidase Pyridoxal PO4 = pyridoxal phosphate, pyridoxal-5-phosphate (P5P) Adapted from Pearl.  J Inhe...
(P5P) (P5P) From Pearl.  Genereviews. http://www.genetests.org/
Schematic of ionotropic glutamate receptors:  Non-NMDA (AMPA/Kainate) and NMDA.  Note glycine and Mg binding sites in the ...
Schematic of GABA A  receptor:  typical ionotropic receptor.  Heteropentameric structure.  Forms pore for Cl -  flux.  Kan...
NMDA receptor: note glycine functions as a co-agonist  (source:  Nature )
Epileptic encephalopathy due to non-ketotic hyperglycinemia
Epileptic encephalopathy due to non-ketotic hyperglycinemia
PNDs involving disturbances of amino acid neurotransmission <ul><li>Pyridoxine responsive seizures </li></ul><ul><ul><li>A...
Clinical patterns potentially warranting evaluation for PNDs <ul><li>Early childhood refractory epilepsies </li></ul><ul><...
Clinical conditions warranting evaluation for PNDs <ul><li>Early childhood refractory epilepsies </li></ul><ul><ul><li>Neo...
Clinical conditions warranting evaluation for PNDs <ul><li>Motor impairments: </li></ul><ul><li>Movement disorders: </li><...
Clinical conditions warranting evaluation for PNDs <ul><li>Developmental delay </li></ul><ul><li>Particularly if unexplain...
Conclusions <ul><li>PNDs rare disorders  </li></ul><ul><li>Due to impairment of neurotransmitter metabolism </li></ul><ul>...
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From Synapse to Symptom: an overview of pediatric ...

  1. 1. From Synapse to Symptom: an overview of pediatric neurotransmitter disorders F Filloux, MD Nov 2009
  2. 2. Disclosures <ul><li>none </li></ul>
  3. 3. Pediatric Neurotransmitter Disorders??? <ul><li>Definition of concept </li></ul><ul><li>Overview of CNS neurotransmitters </li></ul><ul><li>Neuromodulation </li></ul><ul><ul><li>Monoamines and serotonin </li></ul></ul><ul><li>Excitation and inhibition: </li></ul><ul><ul><li>Glutamate, GABA and glycine </li></ul></ul><ul><li>Clinical clues </li></ul>
  4. 4. PNDs: Definition(s) <ul><li>Most pediatric neurological disorders are “neurotransmitter disorders” </li></ul><ul><li>Term refers more specifically to: </li></ul><ul><ul><li>Rare inherited diseases </li></ul></ul><ul><ul><li>Directly interfere with synthesis, metabolism or optimal utilization of neurotransmitters (or are postulated to do so) </li></ul></ul><ul><ul><li>Affect children </li></ul></ul>
  5. 5. PNDs: <ul><li>Disorders of monoamine metabolism </li></ul><ul><ul><li>GTP-cyclohydrolase deficiency (Segawa disease) </li></ul></ul><ul><ul><li>Aromatic L-amino acid decarboxylase deficiency </li></ul></ul><ul><ul><li>Tyrosine hydroxylase deficiency </li></ul></ul><ul><li>Disorders related to  -aminobutyric acid (GABA) function </li></ul><ul><ul><li>Pyridoxine dependency (seizure disorder) </li></ul></ul><ul><ul><ul><li>Folinic acid responsive seizure disorder </li></ul></ul></ul><ul><ul><li>Pyridoxal-phosphate dependency (PNPO deficiency) </li></ul></ul><ul><ul><li>Succinic semialdehyde dehydrogenase (SSADH) deficiency </li></ul></ul><ul><ul><li>GABA transaminase deficiency </li></ul></ul><ul><li>Disorders related to glycine metabolism </li></ul><ul><ul><li>Non-ketotic hyperglycinemia </li></ul></ul>
  6. 6. <ul><li>Overview of neurotransmitters and neuro-transmission </li></ul>
  7. 7. Two major forms of “neurotransmission” <ul><li>Depend on two major types of receptors: </li></ul><ul><li>Ionotropic </li></ul><ul><ul><li>Open ion channels </li></ul></ul><ul><ul><ul><li>Na + , Ca ++ , Cl - (change membrane polarity) </li></ul></ul></ul><ul><li>Metabotropic </li></ul><ul><ul><li>Coupled to G-proteins (G i , G s , G k ) </li></ul></ul><ul><ul><ul><li>Downstream intracytoplasmic metabolic processes </li></ul></ul></ul>
  8. 8. Ionotropic vs. metabotropic effects <ul><li>Open/close (gate) ion channels </li></ul><ul><li>“ Fast” effects </li></ul><ul><ul><li>milliseconds </li></ul></ul><ul><li>Change postsynaptic membrane polarity </li></ul><ul><ul><li>depolarization or hyperpolarization </li></ul></ul><ul><li>“ Focused” synaptic connections </li></ul><ul><li>Glutamate, GABA, glycine, others… </li></ul><ul><li>Act at G-protein coupled receptors </li></ul><ul><li>“ Slow” effects </li></ul><ul><ul><li>Seconds to minutes </li></ul></ul><ul><li>Affect postsynaptic metabolism </li></ul><ul><ul><li>cAMP , calcium mobilization, PI turnover </li></ul></ul><ul><li>“ Diffuse” synaptic connections </li></ul><ul><li>Monoamines, neuropeptides, others.. </li></ul>“ Classical Neurotransmission” “Neuromodulation”
  9. 9. But… there is considerable overlap <ul><li>Glutamate/GABA act at both ionotropic and metabotropic receptors </li></ul><ul><ul><li>GABA A – Cl Channel; GABA B – metabotropic </li></ul></ul><ul><li>Metabotropic receptors may influence K-channel activity </li></ul><ul><ul><li>G K opens K channels  membrane stabilization </li></ul></ul>
  10. 10. From Kandel, Schwartz, Jessell, Principles of Neural Science, 2000.
  11. 12. Diagram of typical metabotropic receptor. Note 7 transmembrane domains; intracytoplasmic loop between 5-6 th lC domains provides binding to G protein
  12. 13. Schematic of G-protein: Activation of metabotropic receptor results in phosphorylation of GDP on alpha subunit. Activated alpha subunit binds to and activates 2 nd messenger system. From Milligan, 1998.
  13. 14. Schematic of metabotropic receptor. Binding of agonist (glutamate) results in phosphorylation of the G-protein and resultant activation of Phospholipase C and PI turnover From Kandel, Schwartz et al., Principles of Neural Science, 2000
  14. 15. Simplistic correlation: <ul><li>Think of </li></ul><ul><li>Monoamine disorders  metabotropic, modulatory </li></ul><ul><ul><li>Movement disorders, dystonia, hypotonia, motor impairments with/without encephalopathy </li></ul></ul><ul><li>Amino acid neurotransmitters  on/off, excitation inhibition </li></ul><ul><ul><li>Intractable seizures in early infancy </li></ul></ul>
  15. 16. Monoaminergic pathways <ul><li>Dopamine (DA), norepinephrine (NE), serotonin (5-HT) </li></ul><ul><li>Arise in brainstem/mesencephalon </li></ul><ul><li>Project more or less widely to forebrain </li></ul><ul><li>**these are neuromodulators </li></ul>
  16. 17. http://content.answers.com/main/content/img/oxford/Oxford_Mind/0198162246.parkinsons-disease.2.jpg Dopaminergic pathways of human brain
  17. 18. Origin of dopaminergic projections Normal Parkinson Disease Adapted from: http://www.mdvu.org/images/par_path1.jpg
  18. 19. Axial brain sections at level of rostral substantia nigra and basal ganglia.
  19. 20. Coronal brain sections at level of Caudate, putamen and globus pallidus. Plate B includes subthalamic nucleus (STN) and rostral substantia nigra (SN). STN SN
  20. 21. Immunofluorescence of a DA cell from the VTA. Note the distal process and long ramification. DA is often released from axonal regions relatively distal from target dendrites and synpatic specializations. DA diffuses to these targets relatively long distances (in comparison to direct synaptic activation at excitatory gluatmatergic synapses for example). This results in a broader, more diffuse effect. Result is that DA may be “excitatory” or “inhibitory” depending on the receptors on target membranes and the function of the target neurons. From:; from Sven Kroener as found in Lapish et al (2006) . http:// www.scholarpedia.org/article/Dopamine_anatomy
  21. 22. Influence of dopamine (DA) on output of the caudate/putamen. Open arrows, excitatory; black arrows, inhibitory. Net effect of CPu is inhibition of VL thalamus and modulatory influence on cortex. With loss of DA influence, there is disinhibition (Direct pathway) and excitation (indicrect pathway) of GPi with resultant excessive inhibition of VL thalamus and insufficient excitation of motor cortex with resultant motor impairments (Parkinsonism, dystonia)
  22. 23. Noradrenergic pathways of human brain. Primary origin of forebrain NE is from the locus ceruleus in the dorsal pons. http://stahlonline.cambridge.org/content/ep/images/85702c07_fig9.jpg
  23. 24. Locus ceruleus Origin of forebrain noradrenergic projection
  24. 25. Serotonin pathways in human brain … http://www.wellspringchiro.com/ws3_serotonin.jpg
  25. 26. Catecholamine synthesis: Rate limiting step is first step, tyrosine hydroxylase. Tetrahydrobiopterin is co-factor for TH.
  26. 28. HVA HIAA MHPG Tyr Trp Phe 3-OMD Monoamine Synthesis Adapted from Hyland, Swoboda and others GTP Cyclohydrolase Neopterin
  27. 29. PNDs 2 e to Disturbances in Monomaminergic transmission <ul><li>GTP cyclohydrolase deficiency </li></ul><ul><ul><li>Segawa disease= dopa responsive dystonia= dystonia with diurnal fluctuation </li></ul></ul><ul><li>L-Aromatic amino acid decarboxylase deficiency (AADC deficiency) </li></ul><ul><li>Tyrosine hydroxylase deficiency </li></ul><ul><li>Other extremely rare conditions </li></ul>* These are largely motor disorders
  28. 30. Excitation vs. Inhibition N- CH- CH2- CH2- COOH N- CH- CH2- CH2- COOH COOH H H H H Glutamic Acid GABA Glutamic acid decarboxylase (cofactor= pyridoxal-5-phosphate)
  29. 31. Pyridoxal-5- phosphate
  30. 32. PNPO = pyridox(am)ine oxidase Pyridoxal PO4 = pyridoxal phosphate, pyridoxal-5-phosphate (P5P) Adapted from Pearl. J Inherit Metab Dis 32:208, 2009.
  31. 33. (P5P) (P5P) From Pearl. Genereviews. http://www.genetests.org/
  32. 34. Schematic of ionotropic glutamate receptors: Non-NMDA (AMPA/Kainate) and NMDA. Note glycine and Mg binding sites in the latter. From Kandel, Schwartz…Principles of Neural Science, 2000.
  33. 35. Schematic of GABA A receptor: typical ionotropic receptor. Heteropentameric structure. Forms pore for Cl - flux. Kandel, Schwartz, Jessell, 1991
  34. 36. NMDA receptor: note glycine functions as a co-agonist (source: Nature )
  35. 37. Epileptic encephalopathy due to non-ketotic hyperglycinemia
  36. 38. Epileptic encephalopathy due to non-ketotic hyperglycinemia
  37. 39. PNDs involving disturbances of amino acid neurotransmission <ul><li>Pyridoxine responsive seizures </li></ul><ul><ul><li>ALDH7A1 gene mutations ( Antiquitin def) </li></ul></ul><ul><li>Pyridoxal phosphate responsive seizures </li></ul><ul><ul><li>Pyridox(am)ine phosphate oxidase (PNPO) deficiency </li></ul></ul><ul><li>Folinic acid responsive seizure disorder </li></ul><ul><ul><li>Allelic with pyridoxine responsive seizures </li></ul></ul><ul><li>SSADH deficiency ( succinic semialdhyde dehydrogenase deficiency) </li></ul><ul><li>Non-ketotic hyperglycinemia </li></ul>* all but SSADH deficiency tend to cause early infantile epileptic encephalopathies
  38. 40. Clinical patterns potentially warranting evaluation for PNDs <ul><li>Early childhood refractory epilepsies </li></ul><ul><li>Unexplained motor impairments </li></ul><ul><ul><li>Particularly if early onset, diurnal fluctuation, rigidity-dystonia </li></ul></ul><ul><li>Unexplained global developmental delay </li></ul><ul><ul><li>Particularly with epilepsy, severe expressive language impairment </li></ul></ul><ul><ul><li>especially if associated with autonomic dysfunction </li></ul></ul>
  39. 41. Clinical conditions warranting evaluation for PNDs <ul><li>Early childhood refractory epilepsies </li></ul><ul><ul><li>Neonatal epileptic encephalopathies </li></ul></ul><ul><ul><li>Early Infantile epileptic encephalopathies </li></ul></ul><ul><ul><li>Suppression-burst patterns (EEG) </li></ul></ul><ul><ul><li>Mixed refractory seizures early in childhood </li></ul></ul><ul><ul><li>Unexplained infantile spasms </li></ul></ul><ul><ul><li>Failure to respond to “standard” antiepileptics </li></ul></ul><ul><ul><li>Normal or nonspecific imaging </li></ul></ul><ul><ul><li>Other diagnostic studies unremarkable </li></ul></ul><ul><ul><ul><li>Infectious eval, metabolic studies, genetic studies etc… </li></ul></ul></ul>
  40. 42. Clinical conditions warranting evaluation for PNDs <ul><li>Motor impairments: </li></ul><ul><li>Movement disorders: </li></ul><ul><ul><li>Neonates and infants: </li></ul></ul><ul><ul><ul><li>profound hypotonia, dysphagia, oculogyric crises,convergence spasms, tremor, dystonia, hypertonia, rigidity, spasmodic dystonia </li></ul></ul></ul><ul><ul><li>Older children </li></ul></ul><ul><ul><ul><li>Dystonia, (particularly with diurnal fluctuation) </li></ul></ul></ul><ul><ul><ul><li>“ cerebral palsy” (without explanation, atypical, progressive) </li></ul></ul></ul><ul><ul><ul><li>“ spastic diplegia” (as above) </li></ul></ul></ul>
  41. 43. Clinical conditions warranting evaluation for PNDs <ul><li>Developmental delay </li></ul><ul><li>Particularly if unexplained after thorough evaluation </li></ul><ul><ul><li>plasma AAs, OAs, acyl-carnitine profile, lactate/pyruvate, MRI brain, MR spectroscopy, NH 3 , biotinidase activity, genetic evaluation and microarray +/- other studies </li></ul></ul><ul><li>With profound hypotonia </li></ul><ul><li>With dystonia (oculogyric crises), parkinsonism, tremor, other movement disorders </li></ul><ul><li>With severe expressive language impairment </li></ul><ul><li>With epilepsy </li></ul><ul><li>With autonomic aberrations </li></ul>
  42. 44. Conclusions <ul><li>PNDs rare disorders </li></ul><ul><li>Due to impairment of neurotransmitter metabolism </li></ul><ul><ul><li>Monamines, glutamate, GABA, glycine </li></ul></ul><ul><li>Diagnosis based on clinical features, CSF analysis, genetic testing </li></ul><ul><li>Manifestations are pleiotropic </li></ul><ul><ul><li>Movement disorders, developmental impairment, intractable epilepsy of very early onset </li></ul></ul><ul><li>May mimic more common pediatric neurologic conditions </li></ul>

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