Case 6: MERFF

Question 1

Symptoms of DAVID Santos

Answer 1

seizures at grocery store, generalized spek and slow wave disharctges, gacground sloing
focal epileptiform discharges

Question 2

What diseases need to be ruled out form Dx (4)

Answer 2

1. BEnign neonatal epilespty Type 1 (VG K+ channels KCNQ2) and Type 2 (KCNQ3)
2. GEneralized epilepsy with febrile seizures (na chanel beta1 subunit- SCN1B)
3. Autosomal dominant nocturnal forntola lope epilepsy (neurolgoical nACHR subuntis)
4. Generalized epilepsy with febriel seizures plus type 3- GABAA R (GABRG2)

Question 3

How is the EEG pattern abnormal

Answer 3

awake patern should be beta waves that have constant size and frequency; slow wave complexes and ictal (epileptiform waves are indicative of seizure

Question 4

how long does muscle biopsy take?

Answer 4

24-48 hours

Question 5

Myalgia,

Answer 5

sore muscles

Question 6

Myopathy

Answer 6

lactic acidosis

Question 7

RRF, muscle patholog

Answer 7

sore muscles

Question 8

Myoclonus

Answer 8

Muscle Jerkiness

Question 9

Spasticity

Answer 9

Muscle Stiffness

Question 10

Ataxic gait

Answer 10

specific cerebellar deficit

Question 11

Seiures

Answer 11

epilepsy or other udnerlying metabolic condition

Question 12

High lactate to pyruve (L/P)

Answer 12

suggests block in respiratory chain

Question 13

Atrophy

Answer 13

loss of tissue (brain or muscle)

Question 14

What are alternate Dx to consider beyond Seizure Disorders

Answer 14

MELAS

Friedrich’s ATAXIA

Leigh Disease (Subacute NEcrotizing Encephalomyopathy)

NARP Syndrome

Question 15

What is MELAS

Answer 15

Mitochondiral Myopathy, Encephalopathy, Lactic Acidoss, and STROKE-lik epsidomes

Mutaiton in mtDNA for single base in tRNA

Heteroplasmic and highly variable in expression

does NOT have ragged red fibers (RRF) and show cortical blindness

NO cerbellar signs, myoclonus, heart block, opthalmoplegia, or retinal chages

Question 16

What is mustaiotn in MELAS

Answer 16

patietn is the A-G trnastition at nt3243, a mutaiton in tRNA-LEU

Question 17

Diff betwen MELAS and MERRF

Answer 17

NO RRF!

NO cerebellar sings, myoclonus, heart block, eye cages

Question 18

Friedrich’s ataxia

Answer 18

AUTOSOMAL RECESSIVE ,

spinocerebellar degeneariton

Question 19

what is prevelacne of Frierich’s Ataxia

Answer 19

1/50,000

abnormal gene is Chrosoome 9

Question 20

What is definitive form of Friedreich ataxia?

Answer 20

trinucleotide repeat of GAA, which causes loss of expretion off Frataxin protein

symptom ataxic gait , onset 7-15 years old

Question 21

What clinical triad sugests Dx of Fridrich’s ataxia

Answer 21

1. ataxia
2. areflexia
3. positive Babisnki reflex

Difintieite Dx thorugh DNA testing

progressive diease
Wheelchair bound by 1st or 2nd decade of life

knee jerk relfexes lost

Question 22

Leigh DIsease (Subacute Necrotizing Encehalomyopahty) causes

Answer 22

PDH complex deficiency

Complex I or II deficinecy

Complex IV (COX) de

CObles V (ATPase def)

Def of Coenzyme Q10

Question 23

about 30% of causes of LEigh Diseas are due to what?

Answer 23

tDNA mutaiton

Question 24

when does Leigh Disease become apparent

Answer 24

infancy, swallowign and feelign probles, vomintng, faiglure to thrive

Question 25

generalized symtosm Legh DIsease

Answer 25

general seizures, weakenss, hypotonia, ataxia, tremor pyramidal signs, sighing sobbing

Question 26

NARP syndrome

Answer 26

maternally inherited disorder present with either Leight Syndome or with Neurogenic weakenss and neuropathy, ataxia, reitinits pigmentos (NARP syndome) as well as seizures

Question 27

Cuase of NARP

Answer 27

muation at nt 89933within ATPase subutni 5 gene Severeity of disaase presentaiton correlated wit % of mutatn mtDNA in leukoctes

Question 28

What is MERRF

Answer 28

Myoclonic epilepsy with Ragged Red Fibers affects mucle sna dNS

Question 29

When does MERRF appear?

Answer 29

during childhood or adolescence

Question 30

What are common prsenting signs of MERRF

Answer 30

sponatneous muscle twithces and spasm (myoclonus) Weakness (myopathy) Progressive stiffness (Spasticity)

Question 31

Why do muscles appear to have ragged red dibers

Answer 31

abnormal deposits of mitochondria as irregulat pathces at teh sarcolmma border,es in red muscle fibers NOT foudn in mitochondrial diseas that DO NOT affect respiratory chain- NOT IN LEIGH SYNDOME and can be used to rule out DDx

Question 32

Signs of MERRF

Answer 32

recurrent seizures (epilepsy) Ataxia- difficulty coordinating movments periphearl neuropathy - loss of sensation in extremities dementia0 slow deterioraition of intelliecula fucniton Sensorineural hearing loss or optic nerve atrophy short stature and heart abnormaltyiesy (cardiomyopathy) or maybe iposmas

Question 33

what are multisystem invovlement of MERRF

Answer 33

``` Myoclonic seizures, lactic acidosis, evidence of maternal inheritence, varibale expressivey in teh kindred and a muscle biopsy with RRF distinguish MERRF form othe rconditions ```

Question 34

Can disorder be in somebody with NO family Hx

Answer 34

yes, less comon, but a new mutation in mt gene can occur

Question 35

Prenatal Dx

Answer 35

if mtDNA mutaiton is detected in mother

Question 36

Polyplasmy

Answer 36

mroe than one version of mitochodnrial gene in any cell b/c each mitochondrian contains multiple genomes! when cell divide,s mitochondira nad mtDNA distribute randomly amotn daghter cells

Question 37

Heteropalsmy

Answer 37

mitochodnira in a cell are mixed poultion of WT and muated DNA. Some mtDNA mutaitona re neutral (polymoprhic) but most deleterios (pathogenic) mutaiton are heteroplasmic i

Question 38

Homopalsmicy

Answer 38

all mitochondria in a given cela re the sme

Question 39

Threshold effect

Answer 39

tpically a threshold level below chich cells starte to degenerate and die organ systems with large ATP requriemenst and high thresholds tend to be more seriously affected, such as CNS and msucle cells

Question 40

HOw amny bp are in mtDNA?

Answer 40

~16,000 bp

Question 41

Is there junk DNA or introns in mt?

Answer 41

NO! DNA repair mechaisms foudn in nucleus of cells are not located in mitochondra

Question 42

What are 80% of MERFF causes mutation

Answer 42

heteroplamic G to A mutaiton in nt 8344 of the tRNA lys gene of mtDNA (MT-TK) Additiaonl patients with T tto C mutaiton in 8356 in tNA lys

Question 43

What kind of mutations cause MERRF

Answer 43

single base mutaitons MT-TK, impair abiltity of mitochodnria to make protiens, use oxygen, and produce enegy resutl in increased lactic acid levels

Question 44

Wha tis the rate of mtDNA muatioan

Answer 44

higher than nuclear DNA mutaiotn due to lack of DNA repair machineary in motcohdinra and by damage by ROS andthat are released during ox phos process as ATP roduced

Question 45

How do you establish Dx in a PROBAND

Answer 45

blood leukocyte DNA is insitally screened for m.8344 A> G mutaiton follwoed b y screenign for m.8346T>C, 8363G>A and m8361 G>A mutations DNA form buccal mucosa, mucsle, or urine sediment can be screend for mtDNA

Question 46

What can be doen in simplex cases (singel occurrendce in a fmaily) with mycolcous, epilepsy, and ataxia,

Answer 46

muscle biopsy is useful ins usefull in detecign signs of mitochodnral dysfuction sucha s RRF, cystochom c ox-def ifber,s orbiochemical defects of mito res chian enzymes

Question 47

Social implicatsion

Answer 47

MERRF becomes evident in early childhood (5-1 years old) folwing nromal develpetn