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Neurogenetics Flashcards

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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
facio-scapio-humeral MD (FSHD)
- 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
26
FSH1D testing
- elevated CK <1500 - EMG with myopathic changes - GT following suggestive NM exam
27
FSHD1 genetics
-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
28
congenital myopathies
- 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
29
malignant hyperthermia
-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
30
later onset pompe
- increased risk for brain aneurysm - lower rates of cardiac involvement - responds better to ERT
31
difficult birth and CK
causes increased CK levels
32
EMG
readings of muscle activity obtained when at rest and during contraction
33
SMA testing
- 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
genetic myasthenic syndromes
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
WES and NM disorders
five most common not detectable this way (including dystrophinopathies, SMA, CMT1A)
36
CMTs
- muscle weakness due to neuropathy of motor or sensory nerves - 50 known genes with different types of inheritance - 1 in 2500 incidence overall
37
CMT phenotype
-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
CMT etiology
- 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
CMT1A
- most common form CMT | - contiguous gene duplication of PMP22
40
HNPP
CMT1A counterpart due to deletion in PMP22
41
HD clinical features
-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
HD genetics
-AD mutation of HTT gene +Huntingtin protein required in normal development -CAG repeat expansion (polyglutamine disorder) +GT measures the length of repeats
43
HD repeats
-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
anticipation
earlier or more severe presentation of a condition in successive generations
45
anticipation in HD
- 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
HD GT and GC
-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
neurogenetics visit model
- 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
Alzheimer's dz
-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
Alzheimer's incidence
-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
AD genetics
-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
early AD phenotype
- onset between 20-60y but usually 40s-50s - rapid disease progression between 6-7y - association with seizures, myoclonus, language deficits
52
G206A mutation
PR/DR founder mutation in EOAD
53
APOE e4
-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
parkinson's disease
-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
PD phenotype
-disordered movement, tremors (most common initial sign), rigidity, bradykinesia, postural instability
56
PD genetics and incidence
-~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
PD management
- L-dopa to supplement deficiency | - deep brain stimulation (not everyone is a candidate)
58
PARK2
-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
SNCA
-AD mutation and duplication seen in PD | +codes for alpha-synuclein
60
LRK2
``` -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
GBA
- carrier status seen with increased risk for PD with early onset and dementia - 5 fold increased risk suspected - also implicated in gaucher disease
62
VPS35
- AD mutations associated with PD | - phenotype typically expected to be similar to LOPD
63
MAPT
mutations implicated in FTD
64
FTD
-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
FTD phenotype
- 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
C9orf72
-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
MAPT
-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
GRN
-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
hexanucleotide repeats in C9orf72
- 30+ is considered disease causing | - most patients with over 1000
70
ALS phenotype
- 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
SOD1
-second leading cause of ALS | +3% sporadic cases, 20% familial
72
VCP
mutations should be suspected with any combination of ALS, FTD, paget's disease of bone, and inclusion body myopathy in patients or families
73
Friedrich Ataxia
-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
Friedrich Ataxia alleles
-5-33 GAA repeats-normal -34-65 GAA repeats-premutation +44-66-borderline -66-1300+-full mutation

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