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Neurogenetics Flashcards

1
Q

Gower sign

A
  • individual rolls to side, lifts themself with arms, then legs & has to shuffle up to standing position because they can’t lift themselves
  • key part of neuro PE
  • demonstrates proximal muscle weakness, but not specific to a dx
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2
Q

Trendelenburg gait

A
  • used to identify proximal muscle weakness

- weakness of abductor and gluteus muscles leads to walking abnormalities

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3
Q

DMD

A 
-most common childhood onset MD
\+incidence: 1 in 3500 males
-life shortening-lifespan into 4th decade
-wheelchair bound by age 13y 
-onset 2-4yo
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4
Q

DMD/BMD dx

A

-high ck with clinical features
-EEG-not always performed because it only confirms myopathic disorder
-GT done in two tiers: del/dup before full seq
+also carrier testing b/c 2/3 moms are carriers
-skeletal bx
+invasive so less common, but allows for detection of otherwise non-detectable mutation

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5
Q

BMD

A
  • incidence of 1 in 30000 males
  • preservation of ambulation until 16y, sometimes remain ambulatory
  • onset and lifespan variable
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6
Q

Other dystrophinopathies

A
  • intermediate dystrophinopathy-ambulation loss between 13-16y
  • isolated CM
  • exercise-induced myalgias and muscle cramping
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7
Q

DMD sx

A

-generalized muscle weakness and wasting
+usually hips, pelvic muscles, thighs affected first (proximal)
-DD, toe-walking, and SD, LD may also occur
-static level of cognitive impairment is known
+neuropsych studies show 25-50% boys with specific profile: short term/working memory deficits, limiting verbal capacity and later can develop executive function
-scoliosis develops with ambulation loss
-respiratory insufficiency and CM leading to heart failure

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8
Q

dystrophinopathy management

A
  • use of steroids to reduce scoliosis effects

- followed by near, cardio, pulmonary, ortho and therapy, GI, nutrition, social work

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9
Q

dystrophinopathy dx

A

-muscle bx is gold standard
+abnormal cells, fatty & connective tissue infiltrate
+immunostaining can look for presence/absence of specific protein

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10
Q

DMD/BMD carriers

A

-unaffected from skeletal muscle perspective (<5% have weakness)
+due to skewed X-inactivation
-cardiac function should be monitored
+20% w/LV dilation, 5-8% with DCM

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11
Q

Dystrophin contiguous gene deletion

A
  • entire gene will be deleted
  • rare multi systemic syndrome
  • present early in life with many issues
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12
Q

DMD/BMD mutations

A

-exonic del/dups
+60% DMD; 85-90% BMD
-intragenic mutations account for the rest
+small indwells
+premature stops-15% DMD
+missense and deep intronic variants are rare
-in frame mutations thought to result in BMD, out of frame in DMD-92% compliance to this

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13
Q

LGMD phenotype

A

-progressive proximal muscle weakness and wasting
+can lead to waddling gait, toes walking, sometimes with need for wheelchair assistance later
+Gower sign and running difficulty
-onset from childhood to adulthood
-other affected organ systems in some types:
+CM
+respiratory-nocturnal hypoventilation, respiratory insufficiency
-scapular winging, lordosis, scoliosis, joint contractures

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14
Q

LGMD dx

A

-elevated CK
-dystrophic muscle bx changes
+sometimes staining can give us info into specific subtype

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15
Q

LGMD genetics

A

-disorder has clinically “indistinguishable” subtypes
-heterogeneous
+Types 1A-1H are AD
+Types 2A-2Q are AR

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16
Q

sarcoglycanopathies

A

-refers to LGMD types 2C-2F
-beta and delta (E and F) tend to be most severe, alpha (D) less severe
+30% beta, delta, gamma with CM
-onset variable, often ambulation loss 15y post-dx
+70% childhood onset LGMD, 10% adult onset
-no cognitive effects

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17
Q

myotonic dystrophy 1 (DM1) sx

A

-skeletal and smooth muscle effects
+delayed relaxation of voluntary contraction
+greater distal muscle weakness
-early onset cataracts
-arrhythmias and CMs; tends to be major COD
-DM, hypothyroidism, male infertility due to endocrine dysfunction
-minor LD to severe ID in congenital
-can see polyhydramnios prenatally and contractures

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18
Q

DM1 subtypes

A
  • type 1-mild: cataracts, mild myotonia; onset 20-70y, sometimes lifespan shortened
  • type 2-classic: weakness, arrhythmia, cataracts, balding, cataracts, myotonia; onset 10-30y, lifespan shortened to ~55y
  • type 3-congenital: hypotonia, respiratory deficits, ID, facial diplegia, classic signs later in life; onset between 0-10y with lifespan shortened to ~45y
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19
Q

DM1 genetics

A

-due to triplet repeat expansion of DMPK
-usually inherited from affected mom
-reduced penetrance and anticipation with 60% mildly affected moms having congenital presentation children
-normal alleles contain 5-34 CTG repeats
-premutation: 35-49
-full mutation 50+ repeats
+50- 150 mild
+100-1000 classic
+over 1000 congenital

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20
Q

DM2 genetics

A
  • due to intronic tetra nucleotide (CCTG) expansion of CNBP
  • repeat size 75-11000
  • no anticipation or correlation of phenotype with repeat number
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21
Q

DM2 phenotype

A
  • mytonia, progressive muscle weakness (mostly proximal)
  • early cataracts
  • CM, arrhythmia, conduction block
  • diabetes, hypothyroidism, decreased fertility
  • LD-severe ID
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22
Q

merosin deficient congenital MD

A
  • LAMA2 mutations-two null alleles
  • severe hypotonia and muscle weakness from birth, mild neuropathy
  • high CK (11000s)
  • white matter changes/leukoencephalopathy on MRI
  • no ID, but higher incidence sz
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23
Q

dystroglycanopathies

A

-only due to post transcriptional mutations or would otherwise be embryonic lethal

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24
Q

cobble stone lissencephaly

A

Walker-Warburg syndrome caused by AR in POMT

  • can also polymicrogyria
  • death within 3y
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25
Q

facio-scapio-humeral MD (FSHD)

A
  • one of the most common adult onset MDs, has progressive onset
  • classically affects face, shoulder blade and upper arm, as well as lower leg muscles
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26
Q

FSH1D testing

A
  • elevated CK <1500
  • EMG with myopathic changes
  • GT following suggestive NM exam
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27
Q

FSHD1 genetics

A

-contraction of D4Z4 allele (1-10 repeats v 11-100 nL)
-loss of copies of intron leads to DUX4 acetylation and expression of a gene that is normally silenced on 4qA allele
+no phenotype if 4qB allele
+type 2 due to independent mutation of SMCHD1

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28
Q

congenital myopathies

A
  • genetic heterogeneity makes classic muscle biopsy diagnosis difficult, nL CK
  • neonatal onset, non-progressive, but DDs
  • slender habitus with atrophy, sometimes joint or skeletal differences
  • possible nocturnal hypoventilation
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29
Q

malignant hyperthermia

A

-occurs in 65-75% of individuals with central core disease
-causes transient muscle rigidity, hyperthermia, and rhabdomyolysis
+can be lethal if not treated
-RYR1 mutations cause 50% cases

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30
Q

later onset pompe

A
  • increased risk for brain aneurysm
  • lower rates of cardiac involvement
  • responds better to ERT
31
Q

difficult birth and CK

A

causes increased CK levels

32
Q

EMG

A

readings of muscle activity obtained when at rest and during contraction

33
Q

SMA testing

A
  • EMG: denervated muscle causes diminished action potential amplitude, regular spontaneous motor unit activity
  • muscle bx: denervation with no other changes, grooved atrophy
  • DNA testing: first choice
34
Q

genetic myasthenic syndromes

A

tend to present in infancy, but can present later

  • fatiguable muscle weakness in ocular, bulbar, skeletal and respiratory muscles
  • AD or AR
  • generally treatable with ACHE inhibitors or potassium channel blockers
  • no cognitive involvement
35
Q

WES and NM disorders

A

five most common not detectable this way (including dystrophinopathies, SMA, CMT1A)

36
Q

CMTs

A
  • muscle weakness due to neuropathy of motor or sensory nerves
  • 50 known genes with different types of inheritance
  • 1 in 2500 incidence overall
37
Q

CMT phenotype

A

-progressive distal muscle atrophy and weakness
-hammer toes, high arches, thinning below knees
+note increased involvement of feet over hands
-loss of sensation or proprioception in hands and feet, cramping

38
Q

CMT etiology

A
  • type I/AD: demyelinating dz; low conduction velocity
  • type II/AD: axonal without demyelinating involvement; nL conduction velocity but reduced amplitude
  • type IV/AR: axonal or demyelinating
  • type X: demyelinating
39
Q

CMT1A

A
  • most common form CMT

- contiguous gene duplication of PMP22

40
Q

HNPP

A

CMT1A counterpart due to deletion in PMP22

41
Q

HD clinical features

A

-onset in 4th-5th decade with progression over 10-15y
-involuntary movements (chorea, dystonia, rigidity), gait and swallowing difficulties
+usually first sign
-psychiatric disorders (depression, psychosis, apathy)
-executive function impairment (attention, planning and speech difficulties) with lack of insight and impaired judgement

42
Q

HD genetics

A

-AD mutation of HTT gene
+Huntingtin protein required in normal development
-CAG repeat expansion (polyglutamine disorder)
+GT measures the length of repeats

43
Q

HD repeats

A

-26 or less CAG=nL
-27-35=intermediate/mutable allele
+not usually disease causing but poses risk in future generations, unstable
-36-39=mutation with reduced penetrance
+possible risk for symptoms
-40 or more=full penetrance mutation

44
Q

anticipation

A

earlier or more severe presentation of a condition in successive generations

45
Q

anticipation in HD

A
  • more likely to be related to instability and expansion of CAG repeats in spermatogenesis
  • greater repeat number=earlier onset (inverse age and repeat relationship)
46
Q

HD GT and GC

A

-expected uptake was historically lower
+more often to be young adult females
-testing of minors is not recommended
-psychiatric impact is huge and important for individuals seeking testing to consider their ability to cope
+although most people that have testing do not have adverse outcomes

47
Q

neurogenetics visit model

A
  • pre, draw, disclosure and follow-up model
  • can include multi-disciplinary team
  • follows proper guidelines for testing and counseling to help patients make informed decision
  • usually a support person is recommended for client
48
Q

Alzheimer’s dz

A

-most common, yet specific form of dementia, a progressive degenerative disease that can cause a variety of neurological symptoms
+atrophy of the brain cortex
+hippocampus shrinks
+ventricles swell
-currently only definitively diagnosable by the presence of tau neurofibrillary tangles and beta-amyloid plaques on autopsy
-no treatment or cure

49
Q

Alzheimer’s incidence

A

-1 in 9 (11%) affected individuals over 65y
-5.2M affected Americans
+more cases of affected women, but risks not higher
+AA and Hispanic populations at higher risk
+age and family history increase risk

50
Q

AD genetics

A

-AD mutations of APP, PSEN1 and PSEN2
+PSEN1 most common
+present in 2-3% cases of early onset under 60y
-mutations cause abnormal protein cuts
-mutations most likely to be found in individuals with early onset dz and a relative with early onset dz

51
Q

early AD phenotype

A
  • onset between 20-60y but usually 40s-50s
  • rapid disease progression between 6-7y
  • association with seizures, myoclonus, language deficits
52
Q

G206A mutation

A

PR/DR founder mutation in EOAD

53
Q

APOE e4

A

-correlated with increased LOAD risk and arteriosclerosis
+1 copy=3-4x risk
+2 copies=10-15x risk
-not necessary or sufficient to cause dz development
-thought is that this polymorphism causes earlier onset in individuals whom already have a predisposition for other reasons

54
Q

parkinson’s disease

A

-second most common neurodegenerative disorder after AD
-severe, progressive selective degeneration of dopaminergic neurons in substantia nigra
+creates deficiency in dopamine mediated movement
+Lewy-body (alpha synuclein) dementia

55
Q

PD phenotype

A

-disordered movement, tremors (most common initial sign), rigidity, bradykinesia, postural instability

56
Q

PD genetics and incidence

A

-~1M affected, 1-2% gen pop risk
-increased risk for males, older individuals, people with brain injury
-10-15% inherited, mostly sporadic
+AR, AD, XL inheritance patterns seen; panel testing may be desirable if no family mutation established
+higher risk for mutation with strong family history and younger ages of onset

57
Q

PD management

A
  • L-dopa to supplement deficiency

- deep brain stimulation (not everyone is a candidate)

58
Q

PARK2

A

-AR mutation of this gene in juvenile and EOPD
+younger onset=higher mutation risk
-implicated in a milder course of disease with good response to L-dopa
-less understood neuropathology
-carriers with possible increased LOPD risks

59
Q

SNCA

A

-AD mutation and duplication seen in PD

+codes for alpha-synuclein

60
Q

LRK2

A 
-AD mutations seen in PD
\+penetrance ranges from 30-74%
-most common genetic factor in condition
-G2019S
\+0.5% sporadic cases, 2-6% familial
\+15-20% in AJ fams with PD, 30-40% in NA fams with PD
61
Q

GBA

A
  • carrier status seen with increased risk for PD with early onset and dementia
  • 5 fold increased risk suspected
  • also implicated in gaucher disease
62
Q

VPS35

A
  • AD mutations associated with PD

- phenotype typically expected to be similar to LOPD

63
Q

MAPT

A

mutations implicated in FTD

64
Q

FTD

A

-non Alz dz dementia
-earlier age of onset
-causes progressive changes in language, social behaviors and personality
+can also see PD and ALS-like features
-AD genetic mutations in 15-20% cases

65
Q

FTD phenotype

A
  • changes in personality, judgment, inhibition, mood
  • primary progressive aphasias: loss of speech, word-finding, comprehension
  • corticobasal syndrome, progressive supranuclear palsy, joint ALS or motor neuron disease
66
Q

C9orf72

A

-most common cause of FTD and ALS
+FTD-5% sporadic, 15-20% familial
+ALS-5-10% sporadic, 15-25% familial
-onset around 50s-60s
-can see mixed or single disease phenotypes with variability within same family
+additional connection to psychiatric disorders
-TDP43 positive pathology due to hexanucleotide repeat

67
Q

MAPT

A

-microtuble associated protein tau gene associated with FTD
+accumulation of tau in brain
-AD complete penetrance mutation typically causes onset between 40-60y
-can see any subtype, but no ALS

68
Q

GRN

A

-progranulin
+early termination sequence results in protein haploinsufficiency
+tau negative, TDP43 positive pathology
-AD variable penetrance mutations
+can see onset between 30y-80y
+penetrance is age dependent
-phenotypic variability with parkinsonian like features, no ALS phenotype

69
Q

hexanucleotide repeats in C9orf72

A
  • 30+ is considered disease causing

- most patients with over 1000

70
Q

ALS phenotype

A
  • rapidly progressive neurological disease that attacks nerve cells responsible for controlling voluntary muscles
  • affects of both upper and lower motor neurons leading to loss of voluntary movement, respiratory failure 2-5y from onset
  • see weakening and twitching of muscles
  • 10% of affected individuals survive 10y or more from onset
71
Q

SOD1

A

-second leading cause of ALS

+3% sporadic cases, 20% familial

72
Q

VCP

A

mutations should be suspected with any combination of ALS, FTD, paget’s disease of bone, and inclusion body myopathy in patients or families

73
Q

Friedrich Ataxia

A

-AR mutations of frataxin (FXN)
+abnormal expansion of GAA allele
-typical onset of abnormal gait in late childhood-early adulthood
-development of dysarthria, muscle weakness, lower limb spasticity, loss of lower limb reflexes, bladder dysfunction, loss of position and vibration sensation
-CM, diabetes and hearing issues can also develop
-manage with prostheses and walking aids and/or therapies, can also provide meds for cardio, spasticity, incontinence, insulin management

74
Q

Friedrich Ataxia alleles

A

-5-33 GAA repeats-normal
-34-65 GAA repeats-premutation
+44-66-borderline
-66-1300+-full mutation

ABGC (34 decks)

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