Neurogenetics

Question 1

Describe the different kinds of signs/maneuvers that can help evaluate neuromuscular disease.

Answer 1

Gowers' Maneuver (rolls over to get up from laying down; uses hands to pull up stairs)
Trendelenburg gait (weakness of abductor muscles of lower extremity noted with waddling gait or on stairs)

Question 2

generalized weakness and muscle wasting
generally affects hips, pelvic muscles, and thighs first
first presenting sign may be difficulty climbing stairs or arising from the floor (Grower’s maneuver), though delayed motor milestones, abnormal gait (toe-walking), and speech delays/LD are also seen
some degree of static cognitive impairment (specifically deficits in short-term/working memory; deficits in executive function which takes some time to emerge)
scoliosis develops in most after loss of ambulation
+/- cardiomyopathy
eventually the heart and lungs are also affected leading to respiratory and cardiac failure

Answer 2

DMD associated conditions (general)

Question 3

Describe the difference in onset of Duchenne vs Becker Muscular Dystrophy.

Answer 3

Duchenne- onset of symptoms 2-4 years; wheelchair bound before 13 y/o; lifespan into 4th (sometimes 5th) decade
Becker- onset variable; wheelchair bound >16 y/o (though some remain ambulatory throughout life); lifespan very variable

Question 4

How are DMD associated conditions diagnosed?

Answer 4

Clinical phenotype and elevated CK
Molecular genetic testing (tier 1- CNVs in the dystrophin gene; tier 2- full DMD sequencing; X-linked) - DMD typically is associated with out of frame exonic deletions; in frame exonic deletions typically are associated with BMD
Immunofluorescent staining with dystrophin antibody on muscle biopsy (only if genetic etiology is not found)

Question 5

What kinds of management are recommended for boys with DMD associated conditions.

Answer 5

Chronic, low dose corticosteroids
Follow-ups with GI/nutrition (for dysphagia) and pulmonology (for diaphragmatic dysfunction)
ECHO at diagnosis and periodically as per recommendations of cardiology
Beta blockers/ACE inhibitors (for cardiomyopathy when/if it is identified)
Orthopedic management/rehab/appropriate assistive technology/PT/bracing (these approaches only prolong muscle function)
Psychosocial care
Endocrinology (for growth/adrenal insufficiency/bone health due to the chronic steroid use)

Question 6

What new treatments are now available for DMD associated conditions?

Answer 6

exon skipping (For reading frame deletions- changes from Duchene to Becker by restoring the reading frame) available for exon 51 and exon 53; other exons are in clinical trials
Premature stop-codon read-through (Ataluren/Translarna- aminoglycoside derivative that allows for read-through of early nonsense mutations) ONLY IN EU

Question 7

progressive weakness that begins in the proximal limb muscles (facial and proximal muscle weakness with arms>legs)
onset ranges from childhood to adulthood
elevated CK (2000-5000)
dystrophic changes on muscle biopsy
cardiomyopathy
nocturnal hypoventilation
absence of bulbar symptoms
normal brain MRI and IQ

Answer 7

Limb Girdle Muscular Dystrophy
FKRP LGMID2M, FKTN
AD or AR, but genetically heterogeneous- note that this is typically a purely descriptive diagnosis with many subtypes that are not easily distinguished between

Question 8

progressive weakness that begins in the proximal limb muscles (especially affects the scapular muscles in the early stages)
onset between 3-15 y/o; may loose ambulation on average ~15 years after onset (though some remain ambulatory)
elevated CK
normal intellectual development

Answer 8

Sarcoglycanopathies (LGMD R3-R6)
four distinct genetic causes (not clinically distinguishable)- SGCA, SGCB, SGCG, SGCD
AR (so males and females affected equally)

Question 9

myotonia; delayed relaxation of voluntary contraction
slowly progressive weakness (distal > proximal)
early onset posterior subcapsular cataracts
arrhythmias; cardiomyopathy
diabetes; hypothyroidism; decreased fertility in males
spectrum of learning disabilities to severe ID

Answer 9

Myotonic Dystrophy Type I

Question 10

Describe the three clinical subdivisions of Myotonic Dystrophy Type I.

Answer 10

Mild- likely will only have extra-muscular findings
Classic- extra-muscular findings and spectrum of muscle involvement
Congenital- neuromuscular symptoms from birth/infancy

Question 11

Describe the inheritance of Myotonic dystrophy.

Answer 11

RNA mediated condition
CTG repeat disorder of the DMPK gene-
normal- 5 to 37
premutation- 38 to ~49 (onset 20-70's)
mild- 50 to ~150 (onset 10-30's)
classic- ~100 to ~1000 
congenital- ~1000 to >2000 (nearly all cases are inherited from affected mother who may only have subclinical symptoms)

Question 12

polyhydramnios and decreased fetal movement
Neonatal period-
severe generalized hypotonia multiple joint contractures/arthrogryposis present at birth in some
significant facial diplegia
respiratory insufficiency; prolonged ventilatory support with inability to wean off
Childhood (those that survive)-
gradual improvement of motor function
usually able to walk
myopathy
mild to moderate ID

Answer 12

Congenital Myotonic Dystrophy

Question 13

myotonia; slowly progressive weakness; proximal>distal
early posterior subcapsular cataracts
arrhythmias, AV conduction block, cardiomyopathy (rare)
diabetes, hypothyroidism, decreased fertility in males
NO ID
white matter changes; executive decision-making dysfunction

Answer 13

Myotonic Dystrophy Type 2
intronic tetranucleotide CCTG expansion in the CNBP gene (repeat size 75-11000)
Repeat size cannot predict severity
NO anticipation; repeat size can contract over generations and can expand during lifetime (increases with age)

Question 14

severe hypotonia and weakness at birth
high CK (»1000)
independent walking not achieved in complete deficiency (complete absence of merosin staining on muscle biopsy); ambulation possible with partial merosin deficiency
mild neropathy
white matter changes/leukoencephalopathy on MRI
higher incidence of seizures, but intellectually normal

Answer 14

Merosm Deficient Congenital Muscular Dystrophy
LAMA2
AR
Previously diagnosed on CVS with merosin staining

Question 15

significant hypotonia and weakness; initially contractures not obligatory
absent or temporary ambulation
CK normal to high
characteristic coexistence of very significant distal hyperlaxity and proximal contractures
kyphoscoliosis, torticollis, hip dislocation, talipes
palmar softness, proximal keratosis pilaris, abnormal scars
early respiratory compromise (nocturnal hypoventilation)

Answer 15

Ullrich Congenital Muscular Dystrophy
COL6A1, COL6A2, COL6A3
AR or de novo AD

Question 16

congenital joint contractures and torticollis may be present but often resolve
CK normal to mildly elevated
after initial joint hypermobility, new development of contractures (achilles tendons, elbows, deep finger flexors, pectoralis, quadriceps)
very slow, progressive contractures may become a major problem +/- late loss of ambulation
palmar softness, proximal keratosis pilaris, abnormal scars
restrictive lung disease, nighttime hypoventilation

Answer 16

Bethlem Myopathy
COL6A1, COL6A2, COL6A3
Mostly AD (de novo) but few are AR

Question 17

congenital presentation wtih variable weakness and evolving contractures, high CK
cobblestone lissencephaly (type 2) which can be mistaken for polymicorgyria, abnormal tectum and ponto-cerebellar malformation, hydrocephalus, encephalocele
seizures are common
Lifespan 1-3 years

Answer 17

Walker-Warburg Syndrome

POMT1 (also other genes associated)

Question 18

congenital weakness, progressive contractures and weakness
high CK
cobblestone lissencephaly that can be misread as polymicrogyria; cerebellar dysplasia; abnormal white matter
myopia, optic nerve hypoplasia
seizures (40%); severe ID
cardiomyopathy
respiratory failure
Lifespan ~10 year

Answer 18

Fukuyama Congenital Muscular Dystrophy

Question 19

neonatal hypotonia and variable weakness
high CK
delayed milestones, but may walk
by 5 years deterioration with contractures, weakness, and spasticity
visual impairment (high myopia, cataract, glaucoma, progressively abolished ERG, retinal detachment)
cobblestone lissencephaly that can be “polymicrogyria-like”, occipital agyria, abnormal tectum, pontocerebellar hypoplasia, cerebellar cysts, abnormal white matter
mild to severe ID

Answer 19

Muscle-Eye-Brain disease

POMGnT1 (plus others)

Question 20

severe hypotonia, early selective muscle hypertrophy
high CK
facial and proximal weakness (arms>leg)
respiratory failure and often cardiomyopathy
normal brain imaging
normal to mild ID

Answer 20

Congenital Muscular Dystrophy

FKRP

Question 21

adult onset slowly progressive
face, shoulder, girdle, and upper arms affected
elevated CK (>1500)
myopathic EMG
non-specific myopathic changes on muscle biopsy

Answer 21

Facio-Scapulo-Humeral Muscular Dystrophy
D4Z4 repeat of the DUX4 gene
normal 11-100 units
disease 1-10 units
(gain of function)
MUST happen on 4qA haplotype to be disease causing

Question 22

List the different kinds of “classic: congenital myopathies.

Answer 22

Nemaline myopathy (named for Nemaline rods on muscle biopsy)- mostly AR; some AD
Centronuclear/myotubular myopathy (named for their muscle biopsy characteristic finding)- AD, AR, or XL (MTM1 gene)
Central core disease (“punched out lesion” look in the muscle fibers)- AD or AR
Multi/minicore myopathy (have small central cores on muscle biopsy)- mostly AR, some AD
NOTE- genetically heterogeneous with a broad phenotypic spectrum

Question 23

onset in neonatal period with hypotonia that improves with age
slender habitus, atrophic muscles
delayed motor milestones (though they do improve)
generally non-progressive in childhood
nocturnal hypoventilation possible
typically normal CK

Answer 23

Classic Congenital Myopathies (common phenotype for all genes- difficult to distinguish clinically)
Diagnosed taking into consideration exam with muscle biopsy and/or genetic testing

Question 24

long face, facial weakness, neck weaknes
dysphagia
diaphragmatic involvement
shoulder/arm weakness is more significant than the pelvic/leg weakness

Answer 24

Nemaline myopathy

diagnosed on muscle biopsy (looking for Nimaline rods)

Question 25

variable phenotype with mild to moderate presentation most commonly... mild hypotonia during early infancy delayed motor milestones generalized muscle weakness, quite stable *hip dislocation*, spinal deformities, arched feet, pectus excavatum Severe phenotype is typically lethal Mild is adult onset (almost asymptomatic)

Answer 25

Central core disease

Question 26

severe hypotonia and weakness at birth distal arthrogryposis, congenital fractures respiratory insufficiency (can result in neonatal death); decreased respiratory reserves; frequent infections poor suck and swallow, dysphagia tend to remain non-ambulatory

Answer 26

Central Core Disease- severe neonatal presentation mostly AR in RYR1 gene Muscle biopsy will most often show central cores, more dystrophic changes with less clear cores, or other muscle pathology findings

Question 27

transient muscular rigidity, hyperthermia, rhabdomyolysis that is triggered by halogenated anesthetics, succinylcholine

Answer 27

Malignant Hyperthermia RYR1 gene mutations (50% of cases), CACNA1S, and 4 other loci AD acutely managed with dentrolene Can often be found in association with Central Core disease

Question 28

``` feeding difficulties, failure to thrive hypotonia, reduced movements respiratory infections *hypertrophic cardiomyopathy* enlarged tongue and liver hearing loss *high CK* average onset between 1.6-2 m/o average age at death between 6-8.7 m/o (without treatment) ```

Answer 28

Pompe Disease (GSD II/acid maltase deficiency/acid alpha-glucosidase deficiency) Classic infant form GAA gene AR <1% residual enzyme activity Treatment with Genzyme is less effective than in later onset forms- may require immunomodulating therapy to prevent antibody development

Question 29

distal weakness fatigue muscle cramps heart and liver only sporadically affected aneurysms respiratory and motor dysfunction may not correlate onset from childhood to 60's morbidity and mortality predominantly from respiratory compromise

Answer 29

``` Pompe Disease (GSD II/acid maltase deficiency/acid alpha-glucosidase deficiency) Non-classic childhood/juvenile/adult forms GAA gene AR 1-30% residual enzyme activity Treated with Myozyme/Lumizyme (Genzyme) ```

Question 30

onset prior to 6 months progressive degeneration and loss of the anterior horn cells in the spinal cord and brain stem nuclei severe symmetric muscle weakness and atrophy (though has facial muscle sparing) never sit or roll poor head control, gross motor delays, weight loss due to sucking and swallowing difficulties, and respiratory distress "jug handle position" of arms tongue fasciculations, absence of DTRs death or full time respiratory support by 2 y/o without treatment

Answer 30

Spinal Muscular Atrophy Type 1 SMN1 (95% deletion) AR

Question 31

onset prior to 18 months progressive degeneration and loss of the anterior horn cells in the spinal cord and brain stem nuclei symmetric muscle weakness and atrophy slow gain of motor milestones with ability to sit but never walk independently refusal to bear weight, may sit normal to late, difficulty reaching above head general flacidity postural finger tremor, tongue fasciculations lack of DTRs decreased life expectancy without treatment, typically from respiratory infections

Answer 31

Spinal Muscular Atrophy Type 2 (Dubowitz) SMN1 (95% deletion) AR

Question 32

onset in childhood progressive degeneration and loss of the anterior horn cells in the spinal cord and brain stem nuclei symmetric muscle weakness and atrophy are able to walk, but eventually lose the ability difficulties ascending and descending stairs at 2-3 y/o proximal muscle weakness lower extremities more severely affected than upper depressed/absent DTRs more variable- earlier may have delayed running/jumping; later has falls and fatigue +/- polymyoclonus life expectancy near normal (even without treatment)

Answer 32

Spinal Muscular Atrophy Type 3 (Juvenile/ Kugelberg-Welander) SMN1 (95% deletion) AR

Question 33

present from birth with respiratory failure requiring intubation marked hypotonia minimal spontaneous muscle movements (only with painful stimuli) no suck, gag, or grasp reflexes multiple contractures abnormal echogenicity in streak like pattern in all muscles on US with notable fasciculations death within the first few weeks of life

Answer 33

Spinal Muscular Atrophy Type 0 SMN1 (95% deletion) AR

Question 34

normal milestones onset of weakness after 30 y/o with muscle atrophy tongue fasciculations depressed DTRs very slow progression with no loss of ambulation

Answer 34

Spinal Muscular Atrophy Type 4 (Adult) SMN1 (95% deletion) AR

Question 35

How do we test for Spinal Muscular Atrophy?

Answer 35

Tier 1 test is genetic testing when suspected on physical exam and history EMG and NCV test- gives us information regarding denervation, diminished motor action potential amplitude, regular spontaneous motor unit activity Muscle Biopsy- shows denervation, no other structural abnormalities, no storage material, no dystrophic changes

Question 36

How is SMA treated?

Answer 36

1. Antisense oligonucleotide based treatment (restores exon 7 inclusion in SMN2)- Spinraza/nusinersen (intrathecal injection) vs Evrysdi (oral) 2. gene therapy- Zolgensma/Onasemnogene (AVXS-101) administered by IV injection

Question 37

typically present in infancy or early childhood (rarely in adulthood) fatigable weakness involving ocular, bulbar, and limb muscles CK normal or minimally elevated no cardiac or cognitive involvement positive repetitive stimulation test

Answer 37

Genetic Congenital Myasthenic Syndromes AD or AR some treatable with acetylcholine esterase inhibitors (Mestinon) and/or the potassium channel blocker 3,4-diaminopyridine (3,4-DAP)

Question 38

Distal muscle atrophy and weakness (feet more affected than hands) abnormal sensation (paresthesias, loss, proprioception) 'drop foot' gait, hammertoes, high arches, thinning below the knees

Answer 38

Charcot-Marie-Tooth Disease (peripheral neuropathy disorder) | genetically heterogeneous but phenotype is very similar across all types

Question 39

How are Charcot-Marie-Tooth Diseases classified?

Answer 39

CMT1- demyelinating with AD inheritance (decreased conduction velocities <35 m/s) CMT2- axonal with AD inheritance (conduction velocities normal, but reduced amplitude) CMT4- axonal or demyelinating with AR inheritance CMTX- axonal or demyelinating with XL inheritance

Question 40

symmetric, slowly progressive distal neuropathy (length-dependent progression: fingers and toes affected first) distal muscle weakness and atrophy, weak ankle dorsiflexion, depressed DTRs, pes cavus most remain ambulatory (~5% loose ambulation) mild to moderate distal sensory loss onset between ~5 to 25 y/o

Answer 40

Charcot-Marie-Tooth Syndrome Type 1A 1.4 Mb duplication at 17p12 encompassing PMP22 gene (reciprocal to HNPP) Treated symptomatically with bracing, orthopedic surgery, adaptive shoes, etc) and avoidance of obesity and DM; clinical trials have been thus far unsuccessful

Question 41

episodic paresthesias and numbness triggered by pressure on nerves (such as backpacks) muscle weakness and atrophy that is recurrent and focal age of onset in 2nd or 3rd decade rarely seen with pes cavus

Answer 41

Hereditary Neuropathy with liability to Pressure Palsies | 1.4 Mb deletion encompassing PMP22 gene (reciprocal to CMT1A)

Question 42

Describe the approach to testing for suspected peripheral neuropathy disorders.

Answer 42

Can consider CK level to rule out other kinds of neuromuscular conditions (especially if distal weakness is present without other clear signs) Electrophysiologic studies (EMG/NCV)- delineates between axonal v demyelinating v intermediate neuropathy Genetic testing per electrophys results- Demyelinating- PNP22 del/dup first; if negative, then demyelinating panel, then exome Axonal- panel first; if negative then exome Intermediate- comprehensive peripheral neuropathy panel (CMT) first; if negative then exome

Question 43

lower limb spasticity and weakness (increased tone in certain muscles with weakness in others) +/-hypertonic bladder mild decrease of lower extremity vibration sense onset between childhood to adulthood

Answer 43

``` Uncomplicated Hereditary Spastic Paraplegia (HSP) genetically heterogeneous (MANY genes with all types of inheritance reported) ```

Question 44

``` lower limb spasticity and weakness ataxia seizures cognitive impairment amyotrophy peripheral neuropathy onset between childhood and adulthood ```

Answer 44

``` Complicated Hereditary Spastic Paraplegia (HSP) genetically heterogeneous (MANY genes with all types of inheritance reported) ```

Question 45

How is Hereditary Spastic Paraplegia treated?

Answer 45

Botox for spasticity PT/OT (known to mitigate symptoms) assisted ambulation devices urinary frequency medication (if hypertonic bladder is present)

Question 46

learning and behavioral problems (between 4-10 y/o) progressive cognitive decline dysphagia progressive incoordination new onset adrenal dysfunction survival only a few years after symptom onset (with no treatment)

Answer 46

X-linked Adrenoleukodystrophy- Cerebral Form ABCD1 On NBS Treated with BMT prior to onset of neurological symptoms

Question 47

onset in early adulthood to middle age progressive stiffness and weakness in legs sphincter disturbances; sexual dysfunction +/-changes in behavior and thinking adrenocorticol insufficiency +/-severe neurological compromise Females with mild-moderate spastic paraparesis in middle age or later with typically preserved adrenal function

Answer 47

X-Linked Adrenoleucodystrophy- Adrenomyeloneuropathy Form ABCD1 On NBS

Question 48

``` cerebellar ataxia dysarthria +/-cognitive decline +/-spasticity +/-sensorineural hearing loss +/-retinal findings wide range of severity and age at onset ```

Answer 48

``` Spinocerebellar ataxias (General) significant clinical overlap- typically you will not be able to distinguish each type clinically Genetically heterogeneous with all inheritance types having been described (including repeat expansion)- multiple methods of genetic testing are needed (NGS will not detect most of these variants so you need WGS and repeat expansion testing) Adult onset is usually AD ```

Question 49

Movement (involuntary)-*chorea (non-repetitive, non-periodic jerking of limbs, face, or trunk)*, dystonia, rigidity, slowness, unsteady gait, weight loss Memory- cognitive decline/dementia, difficulty with attention and planning, impaired judgement, lack of insight Mood- personality changes, impulsivity, irritability, anxiety, depression Average age of onset in the 40's with disease duration about 15 years

Answer 49

Huntington Disease HTT gene; CAG repeat disorder with anticipation (expansion especially with paternal inheritance); increased repeats is associated with earlier onset symptoms AD 10-25% have NO family history

Question 50

Describe the repeat levels for Huntington Disease.

Answer 50

``` Normal (unaffected)- <28 repeats Intermediate (unaffected)- 28-35 Reduced-penetrance (may be affected)- 36-39 Full-penetrance (affected)- >40 Juvenile Onset- typically >50 ```

Question 51

``` onset before 20 y/o severe mental deterioration slowness, rigidity, dystonia, muscle spasms (chorea not as common) speech and language delays rapid decline seizures ```

Answer 51

Juvenile Huntington Disease | HTT gene; CAG repeats

Question 52

How is Huntington Disease Diagnosed?

Answer 52

Unified HD Rating Scale (for early and mid stages) assesses (scored 0/normal to 4/severe)... -Motor function (fist hand palm, tongue protrusion, and finger taps) -Cognitive function -Behavioral abnormalities -Functional capacity Natural Progression- - Pre-symptomatic/Stage 0 (free of detectable clinical sign or symptom) - Prodromal/ Stage 1 (subtle changes prior to the actual diagnosis being made, subtle motor signs, minor decline from premorbid level of function but may not be detectable, apathy/depression/behavior changes) - Stage 2 (may still work, mostly independent, may need help with finances and chores) - Stage 3 (no longer able to work, cannot do chores/finances/personal care) - Stage 4 (need 24 hour care) - Stage 5 (largely bedbound; full time nursing requirements)

Question 53

How is Huntington Disease managed?

Answer 53

``` Symptomatic (anti-epileptics, tetrabenazine, benzos can help with chorea; anti-Parkinson drugs can decrease rigidity/slowness BUT increase chorea; PT/OT/ST for gait imbalances and dysphagia; ongoing support and care) Lifestyle (regular schedules; healthy diet and exercise, avoidance of drugs/alcohol) Multidisciplinary approach/HDSA Centers of Excellence (neurology, psychiatry, social work, genetic counseling, therapy, counseling, nutrition) Investigational treatments (gene-silencing with ASO or iRNA; stem cell) ```

Question 54

What is the process of getting HD testing?

Answer 54

Contact 1- Telephone conversation to discuss insurance/protections of GINA, confirm diagnosis in the family/genetic testing results, understand motives Visit 1- genetic counseling including family history (understand their journey/story/preconceived notions and misconceptions), confirm diagnosis, review genetic principles (AD inheritance and risk for pt specifically, general DNA description and CAG repeat, repeat ranges, and review anticipation), risks/benefits/limitations, explore experience and perception, discuss potential burden/reaction; documentation of informed consent, neurological exam (for baseline); mental health assessment (current emotional state, ongoing psych problems/stressors or needs for emotional support, ways to address emergency treatment/support) Visit 2- in person disclosure of results (EARLY in the session); recommend support person during visit (typically someone who is not also at risk or does not have a bias); establish the next mode of contact (ALWAYS at least a telephone reach out to check in) and answer any questions Follow-up- within a few weeks, provide resources PRN, discuss clinical trials, provide additional visits PRN

Question 55

progressive degeneration disease that causes a variety of neurological symptoms (including memory, thinking, and behavior) defined by tau and beta-amyloid plaques on autopsy

Answer 55

Alzheimer's Disease Not well defined genetic etiology at this time (but we do know some potential genetic RISK factors- APOE4 has 3-5 fold increase in hets and 10-15 fold increase in homo- but gender and ethnicity still play a role in risk)

Question 56

Describe the genes that are associated with Early Onset Alzheimer's Disease.

Answer 56

APP (10-15%) PSEN1 (30-70%)- most likely in individuals with onset <60 AND a fhx with EOAD (average age of onset 40-5), rapid progression, can have associated neuro symptoms (seizures myoclonus), G206A Caribbean Hispanic founder mutation PSEN2 (<5%) All are AD and fully penetrant

Question 57

onset 45-65 y/o Changes in behavior (apathy or unwillingness to talk, changes in personality and mood, lack of inhibition or lack of social tact, obsessive behaviors, usually verbal/physical/sexual behaviors) Changes in language (less common but do occur in early stages with difficulty speaking/word finding and eventually leads to virtually mute) Frontal Lobe atrophy, ventricular dilation, some hypocanthal atrophy

Answer 57

Fronto-Temporal Denentia (General) Many subtypes that can all overlap C9orf72*, MAPT*, GRN*, TARDP, VCP, CHMP2B, FUS 20-50% of persons with FTD have a positive family history AD *most important/highly involved genes

Question 58

Describe the subtypes of FTD.

Answer 58

Behavioral Variant (changes in personality, judgement, inhibition, and mood) Primary Progressive Aphagia (loss of speech/word-finding/comprehension) Movement (corticobasal syndrome, progressive supranuclear palsy, FTD with ALS/motor neuron disease)

Question 59

Describe the condition(s) associated with C9orf72.

Answer 59

most common cause of FTD (5% sporadic and 15-20% familial FTD) most common cause of ALS (5-10% sporadic and 25-50% familial ALS) Positive pathogenic variants increases risk for one OR both in the same person Pathology shows TDP-43 protein on autopsy

Question 60

Describe the inheritance pattern associated with C9orf72.

Answer 60

Hexanucleotide repeat (GGGGCC) normal- <30 repeats abnormal- >30 repeats (most individuals who are affected with FTD or ALS have >1000)

Question 61

Describe the condition(s) associated with MAPT.

Answer 61

MAPT (microtubule associated protein tau) is associated with AD fully penetrant FTD with onset 40-60 y/o Variable phenotype with possibility of Parkinsonism Pathology shows abnormal tau protein accumulation in the brain Also associated with Pick's disease

Question 62

Describe the condition(s) associated with GRN.

Answer 62

GRN (Progranulin) gene is associated with FTD (mutations result in early termination/haploinsufficiency) that presents with... Parkinsonism rage of onset 30-80 (average 60 y/o) penetrance may appear reduced due to later onset in some Pathology negative for Tau proteins but positive for TDP-43

Question 63

upper motor neuron signs( hyperreflexia, spasticity) AND lower motor neuron signs (weakness, atrophy, fasciculations) progressive spread to other regions +/- dysarthria and dysphagia average lifespan 2-3 years after clinical dx

Answer 63

Amyotrophic Lateral Sclerosis (ALS) C9orf72 expansions, SOD-1, VCP, TARDBP, several others (FUS, UBQLN2, VCP) AD (some AR and XL have been described) 5-10% of ALS is familial

Question 64

``` tremor stiffness/rigidity slowness/bradykinesia impaired balance and posture loss/decrease of automatic movements (blinking, smiling, swinging arms when walking) speech changes (hypophonia) writing changes (small writing) anosmia constipation, urinary symptoms anxiety/depression, impaired sleep, cognitive impairment orthostatic hypotension ```

Answer 64

Parkinson Disease LRRK2 (AD with RP), GBA (AD with RP), PARK4,5,8,10,17,18 (classic PD; AD- rare), PRKN (AR with early onset), PARK7 (AR with early onset), PARK14 (AR with early onset), PARK15 (AR with early onset), SNCA (AD with early onset) Degeneration of dopaminergic neurons in substantia nigra (creates deficiency in dopamind mediated movements) Pathology shows Lewy bodies (abnormal accumulations of alpha-synuclein)

Question 65

What are the risk factors for PD?

Answer 65

``` males age brain injury toxins genetics (some) first degree relative with PD ```

Question 66

How are PD symptoms treated?

Answer 66

medication (e.g. L-dopa especially good for AR PD) | surgery (deep brain stimulation)

Question 67

Describe the inheritance of PD.

Answer 67

majority is sporadic multifactorial, though recent genetic changes have been identified that can contribute 10-15% familial and 5-10% attributed to variants in single genes (can be AD with full OR reduced penetrance, AR, or X-linked -rare-)

Question 68

Describe the range of onset for PD.

Answer 68

Juvenile: <20 y/o Early onset: 20-50 y/o Adult onset: >50 y/o (typically around 60 y/o)

Question 69

Describe the condition(s) associated with PARK2 (PRKN).

Answer 69

AR, Juvenile and young onset PD Defined by prolonged and milder course of disease than typical PD (and neuropathology not consistent with standard PD) with good response to oral L-dopa carriers may have increased risk of late onset PD

Question 70

Describe the condition(s) associated with SCNA.

Answer 70

SCNA (Alpha-synuclein protein) is a (rare) gene associated with AD Parkinson disease leads to the understanding of the role of alpha-synuclein protein as disease causing in lewy bodies

Question 71

List the genetic causes of hereditary dementia?

Answer 71

``` Parkinson Disease Inherited prion disorders (PRNP) Lewy Bodie Dementia CADASIL and other small vessel diseases Alexander Nieman Pick Fahrs (basal ganglion degeneration disease) Neuroacanthocytosis ```