Neurogenetics Flashcards
Gower sign
- 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
Trendelenburg gait
- used to identify proximal muscle weakness
- weakness of abductor and gluteus muscles leads to walking abnormalities
DMD
-most common childhood onset MD \+incidence: 1 in 3500 males -life shortening-lifespan into 4th decade -wheelchair bound by age 13y -onset 2-4yo
DMD/BMD dx
-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
BMD
- incidence of 1 in 30000 males
- preservation of ambulation until 16y, sometimes remain ambulatory
- onset and lifespan variable
Other dystrophinopathies
- intermediate dystrophinopathy-ambulation loss between 13-16y
- isolated CM
- exercise-induced myalgias and muscle cramping
DMD sx
-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
dystrophinopathy management
- use of steroids to reduce scoliosis effects
- followed by near, cardio, pulmonary, ortho and therapy, GI, nutrition, social work
dystrophinopathy dx
-muscle bx is gold standard
+abnormal cells, fatty & connective tissue infiltrate
+immunostaining can look for presence/absence of specific protein
DMD/BMD carriers
-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
Dystrophin contiguous gene deletion
- entire gene will be deleted
- rare multi systemic syndrome
- present early in life with many issues
DMD/BMD mutations
-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
LGMD phenotype
-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
LGMD dx
-elevated CK
-dystrophic muscle bx changes
+sometimes staining can give us info into specific subtype
LGMD genetics
-disorder has clinically “indistinguishable” subtypes
-heterogeneous
+Types 1A-1H are AD
+Types 2A-2Q are AR
sarcoglycanopathies
-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
myotonic dystrophy 1 (DM1) sx
-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
DM1 subtypes
- 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
DM1 genetics
-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
DM2 genetics
- due to intronic tetra nucleotide (CCTG) expansion of CNBP
- repeat size 75-11000
- no anticipation or correlation of phenotype with repeat number
DM2 phenotype
- mytonia, progressive muscle weakness (mostly proximal)
- early cataracts
- CM, arrhythmia, conduction block
- diabetes, hypothyroidism, decreased fertility
- LD-severe ID
merosin deficient congenital MD
- 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
dystroglycanopathies
-only due to post transcriptional mutations or would otherwise be embryonic lethal
cobble stone lissencephaly
Walker-Warburg syndrome caused by AR in POMT
- can also polymicrogyria
- death within 3y
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
FSH1D testing
- elevated CK <1500
- EMG with myopathic changes
- GT following suggestive NM exam
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
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
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
later onset pompe
- increased risk for brain aneurysm
- lower rates of cardiac involvement
- responds better to ERT
difficult birth and CK
causes increased CK levels
EMG
readings of muscle activity obtained when at rest and during contraction
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
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
WES and NM disorders
five most common not detectable this way (including dystrophinopathies, SMA, CMT1A)
CMTs
- muscle weakness due to neuropathy of motor or sensory nerves
- 50 known genes with different types of inheritance
- 1 in 2500 incidence overall
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
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
CMT1A
- most common form CMT
- contiguous gene duplication of PMP22
HNPP
CMT1A counterpart due to deletion in PMP22
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
HD genetics
-AD mutation of HTT gene
+Huntingtin protein required in normal development
-CAG repeat expansion (polyglutamine disorder)
+GT measures the length of repeats
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
anticipation
earlier or more severe presentation of a condition in successive generations
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)
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
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
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
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
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
early AD phenotype
- onset between 20-60y but usually 40s-50s
- rapid disease progression between 6-7y
- association with seizures, myoclonus, language deficits
G206A mutation
PR/DR founder mutation in EOAD
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
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
PD phenotype
-disordered movement, tremors (most common initial sign), rigidity, bradykinesia, postural instability
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
PD management
- L-dopa to supplement deficiency
- deep brain stimulation (not everyone is a candidate)
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
SNCA
-AD mutation and duplication seen in PD
+codes for alpha-synuclein
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
GBA
- carrier status seen with increased risk for PD with early onset and dementia
- 5 fold increased risk suspected
- also implicated in gaucher disease
VPS35
- AD mutations associated with PD
- phenotype typically expected to be similar to LOPD
MAPT
mutations implicated in FTD
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
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
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
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
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
hexanucleotide repeats in C9orf72
- 30+ is considered disease causing
- most patients with over 1000
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
SOD1
-second leading cause of ALS
+3% sporadic cases, 20% familial
VCP
mutations should be suspected with any combination of ALS, FTD, paget’s disease of bone, and inclusion body myopathy in patients or families
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
Friedrich Ataxia alleles
-5-33 GAA repeats-normal
-34-65 GAA repeats-premutation
+44-66-borderline
-66-1300+-full mutation
