From Synapse to Symptom: an overview of pediatric

neurotransmitter disorders

F Filloux, MD

Nov 2009

Disclosures

none

Pediatric Neurotransmitter Disorders???

Definition of conceptOverview of CNS neurotransmittersNeuromodulation

Monoamines and serotonin

Excitation and inhibition: Glutamate, GABA and glycine

Clinical clues

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

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

Overview of neurotransmitters and neuro-transmission

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

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”

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

From Kandel, Schwartz, Jessell, Principles of Neural Science, 2000.

Diagram of typical metabotropic receptor. Note 7 transmembrane domains; intracytoplasmic loop between 5-6th lC domains provides binding to G protein

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.

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

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

Monoaminergic pathways

Dopamine (DA), norepinephrine (NE), serotonin (5-HT)

Arise in brainstem/mesencephalonProject more or less widely to forebrain

**these are neuromodulators

http://content.answers.com/main/content/img/oxford/Oxford_Mind/0198162246.parkinsons-disease.2.jpg

Dopaminergic pathways of human brain

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 rostral substantia nigra (SN).

STNSN

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

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)

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

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.

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

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

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)

Pyridoxal-5- phosphate

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.

(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 latter.

From Kandel, Schwartz…Principles of Neural Science, 2000.

Schematic of GABAA receptor: typical ionotropic receptor. Heteropentameric

structure. Forms pore for Cl- flux. Kandel, Schwartz, Jessell, 1991

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 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

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

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…

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)

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

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