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Genetics Final > Case 6: MERFF > Flashcards

Case 6: MERFF Flashcards

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1
Q

Symptoms of DAVID Santos

A

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

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2
Q

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

A
  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)
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3
Q

How is the EEG pattern abnormal

A

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

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4
Q

how long does muscle biopsy take?

A

24-48 hours

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5
Q

Myalgia,

A

sore muscles

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6
Q

Myopathy

A

lactic acidosis

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7
Q

RRF, muscle patholog

A

sore muscles

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8
Q

Myoclonus

A

Muscle Jerkiness

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9
Q

Spasticity

A

Muscle Stiffness

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10
Q

Ataxic gait

A

specific cerebellar deficit

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11
Q

Seiures

A

epilepsy or other udnerlying metabolic condition

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12
Q

High lactate to pyruve (L/P)

A

suggests block in respiratory chain

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13
Q

Atrophy

A

loss of tissue (brain or muscle)

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14
Q

What are alternate Dx to consider beyond Seizure Disorders

A

MELAS

Friedrich’s ATAXIA

Leigh Disease (Subacute NEcrotizing Encephalomyopathy)

NARP Syndrome

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15
Q

What is MELAS

A

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

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16
Q

What is mustaiotn in MELAS

A

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

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17
Q

Diff betwen MELAS and MERRF

A

NO RRF!

NO cerebellar sings, myoclonus, heart block, eye cages

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18
Q

Friedrich’s ataxia

A

AUTOSOMAL RECESSIVE ,

spinocerebellar degeneariton

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19
Q

what is prevelacne of Frierich’s Ataxia

A

1/50,000

abnormal gene is Chrosoome 9

20
Q

What is definitive form of Friedreich ataxia?

A

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

symptom ataxic gait , onset 7-15 years old

21
Q

What clinical triad sugests Dx of Fridrich’s ataxia

A
  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

22
Q

Leigh DIsease (Subacute Necrotizing Encehalomyopahty) causes

A

PDH complex deficiency

Complex I or II deficinecy

Complex IV (COX) de

CObles V (ATPase def)

Def of Coenzyme Q10

23
Q

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

A

tDNA mutaiton

24
Q

when does Leigh Disease become apparent

A

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

25
Q

generalized symtosm Legh DIsease

A

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

26
Q

NARP syndrome

A

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

27
Q

Cuase of NARP

A

muation at nt 89933within ATPase subutni 5 gene

Severeity of disaase presentaiton correlated wit % of mutatn mtDNA in leukoctes

28
Q

What is MERRF

A

Myoclonic epilepsy with Ragged Red Fibers

affects mucle sna dNS

29
Q

When does MERRF appear?

A

during childhood or adolescence

30
Q

What are common prsenting signs of MERRF

A

sponatneous muscle twithces and spasm (myoclonus)

Weakness (myopathy)

Progressive stiffness (Spasticity)

31
Q

Why do muscles appear to have ragged red dibers

A

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

32
Q

Signs of MERRF

A

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

33
Q

what are multisystem invovlement of MERRF

A 
Myoclonic seizures, 
lactic acidosis, 
evidence of maternal inheritence, 
varibale expressivey in teh kindred
 and a muscle biopsy with RRF distinguish MERRF form othe rconditions
34
Q

Can disorder be in somebody with NO family Hx

A

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

35
Q

Prenatal Dx

A

if mtDNA mutaiton is detected in mother

36
Q

Polyplasmy

A

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

37
Q

Heteropalsmy

A

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

38
Q

Homopalsmicy

A

all mitochondria in a given cela re the sme

39
Q

Threshold effect

A

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

40
Q

HOw amny bp are in mtDNA?

A

~16,000 bp

41
Q

Is there junk DNA or introns in mt?

A

NO!

DNA repair mechaisms foudn in nucleus of cells are not located in mitochondra

42
Q

What are 80% of MERFF causes mutation

A

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

43
Q

What kind of mutations cause MERRF

A

single base mutaitons MT-TK,

impair abiltity of mitochodnria to make protiens, use oxygen, and produce enegy

resutl in increased lactic acid levels

44
Q

Wha tis the rate of mtDNA muatioan

A

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

45
Q

How do you establish Dx in a PROBAND

A

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

46
Q

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

A

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

47
Q

Social implicatsion

A

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

Genetics Final (8 decks)

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