from synapse to symptom: an overview of pediatric
TRANSCRIPT
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From Synapse to Symptom: an overview of pediatric
neurotransmitter disorders
F Filloux, MD
Nov 2009
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Disclosures
none
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Pediatric Neurotransmitter Disorders???
Definition of conceptOverview of CNS neurotransmittersNeuromodulation
Monoamines and serotonin
Excitation and inhibition: Glutamate, GABA and glycine
Clinical clues
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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
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PNDs:
Disorders of monoamine metabolism GTP-cyclohydrolase deficiency (Segawa disease) Aromatic L-amino acid decarboxylase deficiency Tyrosine hydroxylase deficiency
Disorders related to -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
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Overview of neurotransmitters and neuro-transmission
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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
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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..
“Classical Neurotransmission” “Neuromodulation”
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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
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From Kandel, Schwartz, Jessell, Principles of Neural Science, 2000.
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Diagram of typical metabotropic receptor. Note 7 transmembrane domains; intracytoplasmic loop between 5-6th lC domains provides binding to G protein
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Schematic of G-protein:
Activation of metabotropic receptor results in phosphorylation of GDP on alpha subunit. Activated alpha subunit binds to and activates 2nd messenger system.
From Milligan, 1998.
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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
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Simplistic correlation:
Think ofMonoamine disorders metabotropic,
modulatory Movement disorders, dystonia, hypotonia,
motor impairments with/without encephalopathy
Amino acid neurotransmitters on/off, excitation inhibition Intractable seizures in early infancy
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Monoaminergic pathways
Dopamine (DA), norepinephrine (NE), serotonin (5-HT)
Arise in brainstem/mesencephalonProject more or less widely to forebrain
**these are neuromodulators
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http://content.answers.com/main/content/img/oxford/Oxford_Mind/0198162246.parkinsons-disease.2.jpg
Dopaminergic pathways of human brain
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Origin of dopaminergic projections
Normal
Parkinson Disease
Adapted from: http://www.mdvu.org/images/par_path1.jpg
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Axial brain sections at level of rostral substantia nigra and basal ganglia.
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Coronal brain sections at level of Caudate, putamen and globus pallidus. Plate B includes subthalamic nucleus (STN) and rostral substantia nigra (SN).
STNSN
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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
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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)
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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
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Locus ceruleus
Origin of forebrain noradrenergic projection
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Serotonin pathways in human brain
…http://www.wellspringchiro.com/ws3_serotonin.jpg
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Catecholamine synthesis:
Rate limiting step is first step, tyrosine hydroxylase. Tetrahydrobiopterin is co-factor for TH.
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GTP CTP Cyclohydrolase BH4 DHPR TH TPH PAH qBH2 L-Dopa 5-HTP Tyrosine AADC DA 5HT NE
HVA HIAA
MHPG
Tyr Trp Phe
3-OMD
Monoamine Synthesis
Adapted from Hyland, Swoboda and others
GTP Cyclohydrolase
Neopterin
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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 deficiencyOther extremely rare conditions
* These are largely motor disorders
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Excitation vs. Inhibition
N- CH- CH2- CH2- COOHN- CH- CH2- CH2- COOH
N- CH- CH2- CH2- COOHN- CH- CH2- CH2- COOH
COOHCOOHHH
HH
HH
HH
Glutamic AcidGlutamic Acid
GABAGABA
Glutamic acid decarboxylaseGlutamic acid decarboxylase (cofactor= pyridoxal-5-phosphate)(cofactor= pyridoxal-5-phosphate)
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Pyridoxal-5- phosphate
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Pyridoxine Pyridoxamine (from veggies) (carnivores) kinase kinase PNPO PNPO Pyridoxine-PO4 Pyridoxal-PO4 Pyridoxamine-PO4
Cofactor function
PNPO = pyridox(am)ine oxidase
Pyridoxal PO4 = pyridoxal phosphate, pyridoxal-5-phosphate (P5P)
Adapted from Pearl. J Inherit Metab Dis 32:208, 2009.
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(P5P)
(P5P)
From Pearl. Genereviews. http://www.genetests.org/
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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.
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Schematic of GABAA receptor: typical ionotropic receptor. Heteropentameric
structure. Forms pore for Cl- flux. Kandel, Schwartz, Jessell, 1991
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NMDA receptor: note glycine functions as a co-agonist (source: Nature)
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Epileptic encephalopathy due to non-ketotic hyperglycinemia
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Epileptic encephalopathy due to non-ketotic hyperglycinemia
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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
*all but SSADH deficiency tend to cause early infantile epileptic encephalopathies
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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
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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…
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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)
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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
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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