Idiopathic genetic epilepsies

 

- static, or;

- degenerative

 

Idiopathic - "a disease unto itself"

 

Brain has 20,000,000,000 neurons, each with 10,000-100,000 connections. Most changing organ during development.

 

Epilepsy: propensity for seizures; recurrent unprovoked seizures.

 

- severity and clinical presentation differs with age

- due to single gene or additive threshhold effects

 

STATIC MYOCLONUS EPILEPSIES

 

Infancy, early childhood

 

Benign familial neonatal convulsions

"third day fits"

- family history

- onset of third day, remission in infancy (first month), recurrence 20%

- EEG normal

- typical at arousal, tonic extension with apnea, stare, then blinking and generalized clonic movements

- mutation in KCNQ2 or KCNQ3 gene, part of M type Ca channel

 

Febrile seizures

- not unprovoked, thus not epilepsy

- genetic, runs in families

 

Benign myoclonic epilepsy

- responds well to meds, resolves in years

 

Febrile seizures plus

- more than feb cons

- missense of SCN1A, 1B, 2Q, or GABRG2

 

Severe myoclonic epilepsy

- hard to control

- dev delay if poorly controlled

- nonsense mut of  SCN1A, 1B, 2Q, or GABRG2

 

Myoclonic -astatic epilepsy of Dravet

- myoclonic with drops

- later at 3-5 years age

- also dev dalay if poorly controlled

- missense of  SCN1A, 1B, 2Q, or GABRG2

 

Lennox-Gastaut symptomatic epilepsy continuum

- not idiopathic

- West syndrome - infantile spasms

            - infancy

            - tonic spasms in clusters

            - with regression

            - abnormal - hypsarythmia on EEG

            - ictal EEG - suppression pattern

            - developmental delay

- Lennox-Gastaut syndrome

            - after age 1

            - tonic, atonic, atypical absence, and myoclonic seizures

            - interictal EEG slow, irregular slow spike and wave

            - ictal EEG slow spike wand wave, fast rhythm with tonic seizures during sleep

 

X-linked infantile spasms

- Aristaless- related homeobox gene (ARX)

- family found in Vancouver

 

Childhood, adolesence

 

Febrile sz plus

            - SCN1B, GABRG2

Childhood absence epilepsy

            - CACNA1A, CLCN2

            - normal bkgrd, 3 per second spike and wave , short, no post-ictal

            - provoked by hyperventilation

Juvenile myoclonic epilepsy

            - CACNA1A, CLCN2, GABRA1, CACNB4, EFHC1 (myoclonin) with Ca do main and is pro-apoptotic

            - normal bkgrd, ictal generalized polyspike waves

            - provoked by photic stimuli

Grand mal seizures

 

Genes, combinations of genes involved as well.

 

Focal onset genetic epilepsies

 

Autosomal dominant nocturnal frontal lobe epilepsies

- hypermotor seizures at night

- affects cholinergic sodium channels

 

Benign epilepsy of childhood with centrotemporal spikes (Rolandic)

- mostly benign

- starts in face, speech

- 15q14, 16p12-q12

 

Autosomal dominant lateral temporal lobe epilepsy

- starts in areas for hearing, buzzing sound

- LGI1 (LEU-rich glioma-inactivated gene) TM protein, not ion channel

 

Mesial temporal lobe epilepsy

- gene not found yet

 

PROGRESSIVE MYOCLONUS EPILEPSIES

 

Neuronal ceroid lipofuscinoses (NCL)

            - 9 genes, most common CLN1-3 and CLN6

            - CLN1- usually infantile, 6mo-37yr

                        - cognitive/motor decline, seizures, visual loss at same time

                        - stereotypy

                        - pathology on muscle/skin- GROD (granular osmiophilic deposits)

                        - palmitoyl protein thioesterase (lysosomal deacylator) mutation. Also found in synaptic vesicle

            - CLN2- late infantile, 2-8yr

                        -  resistant seizures first, before decline and visual loss

                        - pathology - primarily curvilinear profiles

                        - tripeptide peptidase mut (in lysosome)

            - CLN3- juvenile, 4-10yr (Batten's disease)

                        - visual loss first before decline and seizures

                        - pathology - primarily fingerprint profiles, vacuolated lymphocytes

                        - TM protein in synaptosomes

            - CLN6 - 2-8yr, several ethnic grps

                        - decline first, before sz and visual loss

                        - pathology - fingerprint, rectilinear, curvilinear

                        - TM protein

 

Unverricht-Lundborg disease

            - most common PME  

            - EPM1 gene - cystatin B protein, inhibits cysteine lysosomal proteases, dodecamer expansion mutation

            - most benign, slow progressive, mild dementia, mild seizures

            - prominant action myoclonus, cerebellar findings

            - Ramsay-Hunt

            - DO NOT GIVE DILANTIN - kills their purkinje cells

            - dx by Southern blots

 

Lafora disease

            - at least 2 genes

            - Lafora bodies in neurons, juxtanuclear or dendrites (mostly), made of fibrillar polyglucosans (starch), which deposits unlike glycogen which is soluble. (Neurons cannot break glycogen.) Related to location of GLC-6-phosphatase (dendrites, zone 1 hepatocytes, eccrine gland ducts)

            -  skin biopsy - seen in sweat glands, both eccrine gland ducts and apocrine gland myoepithelium, don't use armpits because apocrine material looks the same as Lafora bodies.

            - also common in dogs

 

Sialidosis (Type I)

            - neuraminidase deficiency

 

Myoclonic epilepsy with ragged red fibers (MERRF)

            - at lest 2 mitochondrial genes

 

Neuronopathic Gaucher disease