Case 6: MERFF Flashcards
Symptoms of DAVID Santos
seizures at grocery store, generalized spek and slow wave disharctges, gacground sloing
focal epileptiform discharges
What diseases need to be ruled out form Dx (4)
- BEnign neonatal epilespty Type 1 (VG K+ channels KCNQ2) and Type 2 (KCNQ3)
- GEneralized epilepsy with febrile seizures (na chanel beta1 subunit- SCN1B)
- Autosomal dominant nocturnal forntola lope epilepsy (neurolgoical nACHR subuntis)
- Generalized epilepsy with febriel seizures plus type 3- GABAA R (GABRG2)
How is the EEG pattern abnormal
awake patern should be beta waves that have constant size and frequency; slow wave complexes and ictal (epileptiform waves are indicative of seizure
how long does muscle biopsy take?
24-48 hours
Myalgia,
sore muscles
Myopathy
lactic acidosis
RRF, muscle patholog
sore muscles
Myoclonus
Muscle Jerkiness
Spasticity
Muscle Stiffness
Ataxic gait
specific cerebellar deficit
Seiures
epilepsy or other udnerlying metabolic condition
High lactate to pyruve (L/P)
suggests block in respiratory chain
Atrophy
loss of tissue (brain or muscle)
What are alternate Dx to consider beyond Seizure Disorders
MELAS
Friedrich’s ATAXIA
Leigh Disease (Subacute NEcrotizing Encephalomyopathy)
NARP Syndrome
What is MELAS
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
What is mustaiotn in MELAS
patietn is the A-G trnastition at nt3243, a mutaiton in tRNA-LEU
Diff betwen MELAS and MERRF
NO RRF!
NO cerebellar sings, myoclonus, heart block, eye cages
Friedrich’s ataxia
AUTOSOMAL RECESSIVE ,
spinocerebellar degeneariton
what is prevelacne of Frierich’s Ataxia
1/50,000
abnormal gene is Chrosoome 9
What is definitive form of Friedreich ataxia?
trinucleotide repeat of GAA, which causes loss of expretion off Frataxin protein
symptom ataxic gait , onset 7-15 years old
What clinical triad sugests Dx of Fridrich’s ataxia
- ataxia
- areflexia
- positive Babisnki reflex
Difintieite Dx thorugh DNA testing
progressive diease
Wheelchair bound by 1st or 2nd decade of life
knee jerk relfexes lost
Leigh DIsease (Subacute Necrotizing Encehalomyopahty) causes
PDH complex deficiency
Complex I or II deficinecy
Complex IV (COX) de
CObles V (ATPase def)
Def of Coenzyme Q10
about 30% of causes of LEigh Diseas are due to what?
tDNA mutaiton
when does Leigh Disease become apparent
infancy, swallowign and feelign probles, vomintng, faiglure to thrive
generalized symtosm Legh DIsease
general seizures, weakenss, hypotonia, ataxia, tremor pyramidal signs,
sighing sobbing
NARP syndrome
maternally inherited disorder present with either Leight Syndome or with Neurogenic weakenss and neuropathy, ataxia, reitinits pigmentos (NARP syndome) as well as seizures
Cuase of NARP
muation at nt 89933within ATPase subutni 5 gene
Severeity of disaase presentaiton correlated wit % of mutatn mtDNA in leukoctes
What is MERRF
Myoclonic epilepsy with Ragged Red Fibers
affects mucle sna dNS
When does MERRF appear?
during childhood or adolescence
What are common prsenting signs of MERRF
sponatneous muscle twithces and spasm (myoclonus)
Weakness (myopathy)
Progressive stiffness (Spasticity)
Why do muscles appear to have ragged red dibers
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
Signs of MERRF
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
what are multisystem invovlement of MERRF
Myoclonic seizures, lactic acidosis, evidence of maternal inheritence, varibale expressivey in teh kindred and a muscle biopsy with RRF distinguish MERRF form othe rconditions
Can disorder be in somebody with NO family Hx
yes, less comon, but a new mutation in mt gene can occur
Prenatal Dx
if mtDNA mutaiton is detected in mother
Polyplasmy
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
Heteropalsmy
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
Homopalsmicy
all mitochondria in a given cela re the sme
Threshold effect
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
HOw amny bp are in mtDNA?
~16,000 bp
Is there junk DNA or introns in mt?
NO!
DNA repair mechaisms foudn in nucleus of cells are not located in mitochondra
What are 80% of MERFF causes mutation
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
What kind of mutations cause MERRF
single base mutaitons MT-TK,
impair abiltity of mitochodnria to make protiens, use oxygen, and produce enegy
resutl in increased lactic acid levels
Wha tis the rate of mtDNA muatioan
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
How do you establish Dx in a PROBAND
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
What can be doen in simplex cases (singel occurrendce in a fmaily) with mycolcous, epilepsy, and ataxia,
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
Social implicatsion
MERRF becomes evident in early childhood (5-1 years old) folwing nromal develpetn
