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Random Notes : Lakshya j Basumatary, MD.

drbasumatary@gmail.com

Mechanisms of Neurologic Diseases:

One-third of the 35,000 genes encoded in the human genome are expressed in
the nervous system. Each mature brain is composed of 100 billion neurons,
several million miles of axons and dendrites, and >1015 synapses.

Calcium channel disorders


Episodic ataxia-2 CACNL1A
Spinocerebellar ataxia-6 Ca CACNL1A
Familial hemiplegic migraine 1 Ca CACNL1A
Hypokalemic periodic paralysis Ca CACNL1A3
Cerebellar ataxia Ca (P/Q type)
Lambert-Eaton syndrome Ca (P/Q type)

K channel disorders
Episodic ataxia-1 KCNA1
Benign neonatal familial convulsions KCNQ2, KCNQ3
Jorvell and Lange-Nielsen syndrome (deafness, prolonged QT interval, and
arrythmia) KCNQ1, KCNE1
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Autosomal dominant progressive deafness KCNQ4

Sodium channel disorders


Familial hemiplegic migraine 2 SCN1A
Generalized epilepsy with febrile convulsions plus SCN1B
Hyperkalemic periodic paralysis SCN4A
Paramyotonia congenita SCN4A

Chloride channel disorder


Myotonia congenita Cl CLCN1

Principal Classic Neurotransmitters

Acetylcholine (ACh)

Motor neurons in spinal cord neuromuscular junction


Acetylcholinesterases (nerve gases)
Myasthenia gravis (antibodies to ACh receptor)
Congenital myasthenic syndromes (mutations in ACh receptor subunits)
Lambert-Eaton syndrome (antibodies to Ca channels impair ACh release)
Botulism (toxin disrupts ACh release by exocytosis)

Basal forebrain widespread cortex


Alzheimer's disease (selective cell death)
Autosomal dominant frontal lobe epilepsy (mutations in CNS ACh receptor)

Interneurons in striatum Parkinson's disease (tremor)


Autonomic nervous system (preganglionic and postganglionic sympathetic)

Norepinephrine (NE)
Locus coeruleus (pons) limbic system, hypothalamus, cortex----Mood
disorders (MAOA inhibitors and tricyclics increase NE and improve depression)
Medulla locus coeruleus, spinal cord--- Anxiety
Postganglionic neurons of sympathetic nervous system----
Orthostatic tachycardia syndrome (mutations in NE transporter)
Serotonin

Pontine raphe nuclei widespread projections-- Mood disorders (SSRIs improve


depression)

Migraine pain pathway


Medulla/pons dorsal horn of spinal cord -- Pain pathway

GABA
Major inhibitory neurotransmitter in brain;
widespread cortical interneurons and long projection pathways –
Stiff person syndrome (antibodies to glutamic acid decarboxylase, the
biosynthetic enzyme for GABA)

Epilepsy (gabapentin and valproic acid increase GABA)

Glycine
Major inhibitory neurotransmitter in spinal cord –
Spasticity
Hyperekplexia (myoclonic startle syndrome) due to mutations in glycine

receptor
Glutamate
Major excitatory neurotransmitter; located throughout CNS, including cortical
pyramidal cells—

Seizures due to ingestion of domoic acid (a glutamate analogue)


Rasmussen's encephalitis (antibody against glutamate receptor 3)
Excitotoxic cell death

Addictive drugs share the property of increasing dopamine release in the nucleus
accumbens.

A single oligodendrocyte usually ensheaths multiple axons in the central nervous


system (CNS), whereas in the peripheral nervous system (PNS) each Schwann cell
typically myelinates a single axon.

Proteins restricted to CNS myelin—PLP, MOG


Proteins of PNS myelin are-- Po, CX32. PMP22
Proteins present in both CNS and PNS are—GM1, MAG, GQ1b

In the CNS, the X-linked allelic disorders, Pelizaeus-Merzbacher disease and


one variant of familial spastic paraplegia, are caused by mutations in the gene
for proteolipid protein (PLP) that normally promotes extracellular compaction
between adjacent myelin lamellae.

The homologue of PLP in the PNS is the P0 protein, mutations in which cause
the neuropathy Charcot-Marie-Tooth disease (CMT) type 1B.

The most common form of CMT is the 1A subtype caused by a duplication of


the PMP22 gene;

Deletions in PMP22 are responsible for another inherited neuropathy termed


hereditary liability to pressure palsies.

Autoantibodies against myelin gangliosides GQ1b in the Fisher variant of Guillain-


Barré syndrome
GM1 in multifocal motor neuropathy, and

Sulfatide constituents of myelin-associated glycoprotein (MAG) in peripheral


neuropathies associated with monoclonal gammopathies.

EEG

Alpha rhythm 8-13 hz, normal, lying quietly, eyes closed.


Beta rhythm >13 hz when eyes are open
Theta wave – in light sleep 4-7 hz

Hyperventilation 3-4 minute


EEG may be normal in SPS or CPS
Presence of epileptiform activity in EEG is not specific for epilepsy.
Interictal EEG is normal in 60% pt with epilepsy
Coma – nonreactive--burst suppression pattern
Electrocerebral silence – hypothermia, drugs, brain death