Neurogenetics

Question 1

Limb-girdle muscular dystrophies (LGMD)

Answer 1

Type 1 = AD inheritance, type 2 = AR inheritance
Proximal muscle weakness in the shoulder and pelvic girdles
Variable in age of onset and progression
Some forms may have cardiomyopathy, arrhythmias, or respiratory problems

Question 2

15q dup syndrome

Answer 2

One of the most common cytogenetic anomalies with ASD
Caused by one extra maternally derived copy of of the PWS/Angelman critical region 15q11.2-q13.1
Two mechanisms: isodicentric supernumerary chromosome (idic15) resulting in tetrasomy (80% of cases) OR interstitial duplication resulting in trisomy (20% of cases)
Hypotonia, developmental delay and ID, ASD, epilepsy, minor dysmorphic features

Question 3

16p11.2 deletions

Answer 3

Three groups, group 1 = typical, group 2 = distal
Affects development including speech and language, cognitive abilities (learning, ID), ASD/ADHD, poor weight gain when young and obesity when older, macrocephaly, other related symptoms

Question 4

Dystrophinopathies

Answer 4

Caused by mutations in DMD gene 
X-linked 
Spectrum from mild to severe: 
- Elevated CK and muscle weakness
- DMD-associated DCM
- BMD
- DMD

Question 5

DMD

Answer 5

Symptoms include delayed motor milestones, waddling gait, Gower maneuver, hypertrophic calf muscles, sometimes mild ID/ADHD/learning disabilities
Cardiomyopathy in teenage years
Serum CK >10x normal 
Wheelchair by age 12 
Median survival 24 years

Question 6

BMD

Answer 6

Later-onset muscle weakness
CK >5x normal
Cardiomyopathy in teenage years
Median survival mid 40s

Question 7

Female carriers of DMD/BMD

Answer 7

Some can have symptoms
~15-20% have mild-moderate muscle weakness
Elevated CK 2-10x normal
Increased risk for DCM

Question 8

DMD-associated DCM

Answer 8

Left ventricular dilation and congestive heart failure
Males present between 20-40 yrs, progress more rapidly
Females present later

Question 9

Reading frame rule (dystrophinopathies)

Answer 9

Del/dups that preserve the open reading frame (in-frame mutations) cause a milder phenotype
About 10% of mutations do not follow this rule

Question 10

Dystrophinopathy treatment

Answer 10

Multidisciplinary clinics
Antisense oligonucleotides (ASOs)
- Exon skipping
- Stop codon read through

Question 11

Facioscapulohumeral Muscular Dystrophy (FSHD)

Answer 11

Onset childhood to adulthood, >50% have symptoms before age 20
Weakness & atrophy in face (more lower), eyes, shoulder blades, upper arms, lower leg and hip girdle may be affected
Rarely affects cardiac muscles or breathing
Must have a permissive allele + hypomethylation
Type 1 = AD, 70-90% inherited, shortened D4Z4 + 4qA + hypomethylation
Type 2 = inheritance unclear, usually sporadic, SMCHD1 mutation + 4qA + hypomethylation

Question 12

FSHD Genetics

Answer 12

Long arm of chromosome 4
D4Z4 region: Typically 11+ repeats, hypermethylated (silenced) to keep DUX4 silenced, hypomethylation of this region causes FSHD by muscle damage
SMCHD1: makes protein that plays a role in D4Z4 methylation
4qA/4qB haplotype: 4q subtelomeric region, must have 4qA to have FSHD, pLAM sequence differs between the two
pLAM sequence: regulatory region necessary for DUX4 production, permissive allele = functional pLAM, non-permissive allele = nonfunctional pLAM

Question 13

Spinal Muscular Atrophy (SMA)

Answer 13

5 clinical types, AR inheritance
Hypotonia, muscle weakness, decline or regression of motor function, loss of ambulation
Affects anterior horn cells
Caused by mutations most commonly in SMN1 and SMN2 genes
SMN2 = milder phenotype because accounts for only 10% of protein production
On the MN NBS for exon 7 deletion
Treatments focus on splicing defects

Question 14

Amyotrophic Lateral Sclerosis (ALS)

Answer 14

Progressive motor neuron disease, loss of muscle movement
Variable onset areas (bulbar vs limb), eventually all muscle groups will be affected
Inherited or sporadic types
Can be isolated or associated with frontotemporal dementia (FTD)
More than 30 susceptibility genes, no single gene cause, most common = C9orf72 hexanucleotide repeat expansion (>30 pathogenic), SOD1, VCP

Question 15

ALS Counseling Considerations

Answer 15

Testing criteria - age of onset, family history?
Asymptomatic genetic testing - follow HD protocol
Disability accommodations for signing consent forms and counseling someone without language
Legal/ethical concerns about who can consent
DNA banking

Question 16

Frontotemporal Dementia (FTD)

Answer 16

Damage to frontal and temporal lobes of the brain
Associated with personality, behavior, and language changes
Behavioral variant: most common, personality changes, apathy, impaired judgement, difficulty in social situations
Nonfluent variant: problems pronouncing words, slurred speech
Semantic variant: difficulty understanding words and sentences, naming people and objects

Question 17

Myotonic dystrophy

Answer 17

Myotonia = inability to relax muscles at will
AD inheritance
DM1 = caused by CTG repeat expansion in DMPK gene
Three types (mild, classic, congenital) based on clinical features
ID, personality traits, GI or endocrine concerns, progressive impairment of lung function
Anticipation observed
DM2 = caused by CCTG repeat within a complex motif in the CNBP gene
Normal: ≤30 CCTG repeats
Pre-mutation vs Pathogenic: ~30-74 CCTG repeats
Pathogenic: ~75-11,000 CCTG repeats
No anticipation and no correlation with repeat size and disease severity
Myotonia and muscle weakness, cataracts, type 2 diabetes, + other features

Question 18

Congenital myopathy: Collagen VI-related myopathy

Answer 18

Group of disorders
Affects skeletal muscle and connective tissue
Genes: COL6A1, COL6A2, and COL6A3

Question 19

Bethlem myopathy

Answer 19

AD inheritance
Can begin in infancy to adulthood, slowly progressive
Muscle weakness & hypotonia, contractures often in childhood

Question 20

Ullrich congenital muscular dystrophy (CMD)

Answer 20

AR inheritance
Severe muscle weakness beginning after birth
Some cannot walk, others become non-ambulatory in childhood
Joint laxity can develop into contractures
Respiratory involvement, may require ventilation

Question 21

Charcot Marie Tooth (CMT)

Answer 21

Peripheral neuropathy due to demyelination, axonal, or both, nerve damage
Sensory = numbness and tingling, balance
Motor = muscle weakness and atrophy, foot drop, pes cavus/hammertoes
Many types labeled with numbers, based on nerve conduction studies
Type 1-demyelinating
Type 2-axonal
Types 3 and 4-mixed
Subtypes labeled with letters after genetic testing

Question 22

Ataxia Telangiectasia (AT)

Answer 22

Progressive movement disorder, variable presentation
AR Inheritance
ATM gene mutations, carriers have increased cancer risks
SCID NBS detects some affected children
Onset 1-4 years, truncal and gait ataxia, most kids require assistance walking by age 10
Choreoathetosis, myoclonic jerking/tension tremors, progressive slurred speech and difficulty swallowing
Affects eyes, immune system, cancer risk, skin, POF, and other symptoms
Life expectancy 25-50 years

Question 23

Spinocerebellar Ataxias (SCAs)

Answer 23

Group of disorders that cause degeneration of the cerebellum and sometimes the spinal cord
Progressive incoordination of walking
AD Inheritance
Repeat expansion disorders, high penetrance & anticipation are common
Ataxia-poor coordination of movement and balance; poor coordination of hand and eye movements, dysarthria

Question 24

Friedrich Ataxia

Answer 24

Slowly progressive ataxia with onset usually before age 25
Neurologic features, dysarthria, dysphagia, hypertrophic cardiomyopathy, urinary frequency
AR Inheritance
Due to mutations in the FXN gene, most cases due to both alleles with abnormal GAA expansion in intron 1
Normal 5-33
Premutation 34-65
Borderline 44-66
Full penetrance allele 66-1300

Question 25

Neuronal Ceroid Lipofuscinosis (NCL)/ Batten disease

Answer 25

13 types distinguished by gene and age of onset/progression 
Vision loss, epilepsy, and dementia 
Most AR Inheritance
CLN1 = infantile onset 
CLN3 = juvenile onset

Question 26

Huntington’s Disease (HD)

Answer 26

Affects mood, memory, and movement
Typical onset age 30-50, highly variable
Early symptoms can be subtle, may be recognized by someone other than the patient
Caused by CAG repeat expansion in the HHT gene
Anticipation common, mostly paternal
Inverse relationship between disease severity and repeat number

Question 27

SCN1A-related disorders

Answer 27

Spectrum of seizure related disorders
AD Inheritance
Variable presentation, even in the same family
Mild = simple isolated febrile seizures, FS+
Moderate = GEFS+, severe myoclonic epilepsy
Severe = Dravet syndrome and ICE-GTC

Question 28

Dravet syndrome

Answer 28

Develop typically during the first year of life
Frequent and prolonged seizures, many types, drug resistant, may improve after puberty but rarely resolve
Prolonged & uncontrolled seizures lead to developmental delay and cognitive impairment
Decreased lifespan due to seizure induced sudden death or related accidents