Neurogenetics Flashcards
Limb-girdle muscular dystrophies (LGMD)
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
15q dup syndrome
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
16p11.2 deletions
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
Dystrophinopathies
Caused by mutations in DMD gene X-linked Spectrum from mild to severe: - Elevated CK and muscle weakness - DMD-associated DCM - BMD - DMD
DMD
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
BMD
Later-onset muscle weakness
CK >5x normal
Cardiomyopathy in teenage years
Median survival mid 40s
Female carriers of DMD/BMD
Some can have symptoms
~15-20% have mild-moderate muscle weakness
Elevated CK 2-10x normal
Increased risk for DCM
DMD-associated DCM
Left ventricular dilation and congestive heart failure
Males present between 20-40 yrs, progress more rapidly
Females present later
Reading frame rule (dystrophinopathies)
Del/dups that preserve the open reading frame (in-frame mutations) cause a milder phenotype
About 10% of mutations do not follow this rule
Dystrophinopathy treatment
Multidisciplinary clinics
Antisense oligonucleotides (ASOs)
- Exon skipping
- Stop codon read through
Facioscapulohumeral Muscular Dystrophy (FSHD)
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
FSHD Genetics
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
Spinal Muscular Atrophy (SMA)
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
Amyotrophic Lateral Sclerosis (ALS)
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
ALS Counseling Considerations
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
Frontotemporal Dementia (FTD)
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
Myotonic dystrophy
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
Congenital myopathy: Collagen VI-related myopathy
Group of disorders
Affects skeletal muscle and connective tissue
Genes: COL6A1, COL6A2, and COL6A3
Bethlem myopathy
AD inheritance
Can begin in infancy to adulthood, slowly progressive
Muscle weakness & hypotonia, contractures often in childhood
Ullrich congenital muscular dystrophy (CMD)
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
Charcot Marie Tooth (CMT)
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
Ataxia Telangiectasia (AT)
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
Spinocerebellar Ataxias (SCAs)
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
Friedrich Ataxia
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
Neuronal Ceroid Lipofuscinosis (NCL)/ Batten disease
13 types distinguished by gene and age of onset/progression Vision loss, epilepsy, and dementia Most AR Inheritance CLN1 = infantile onset CLN3 = juvenile onset
Huntington’s Disease (HD)
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
SCN1A-related disorders
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
Dravet syndrome
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
