11/11- Neurogenetic Disorders in Pediatrics Flashcards
What are nucleotide repeat disorders?
- Dynamic Mutations
- Developmental and degenerative disorders caused by expansion of unstable repeats
- (These disorders can present in childhood or even infancy)
What are examples of nucleotide repeat disordes?
- Huntington
- Myotonic dystrophy
- FMRI
Where is the Huntington gene located?
- What is the triplet repeat?
- Mapped to 4p
- CAG repeat
Describe Huntington disease
- Symptoms
- Age group
- Disease course
- Inheritance pattern
- Penetrance pattern
- Neurodegenerative disorder
- Affects individuals from childhood to old age
- Most present in mid-life (35-45 years)
- Course of illness varies with age of onset
- Autosomal dominant
- Age-related penetrance
Describe juvenile Huntington Disease
- Onset of symptoms
- What percentage of HD in US
- Childhood vs. teenagers
- Onset of symptoms < 20 yo
- 5-7% of HD in the United States
Childhood (1st decade)
- Developmental delay, frequent falls, clumsiness
- Hyperreflexia, oculomotor disturbances, oral motor dysfunction, marked rigidity, prominent motor and cerebellar symptoms
- 30-50% of juvenile onset have seizures, rapid decline, severe mental deterioration
Teenagers
- Symptoms are more similar to adult HD
- Chorea is a common first symptom
- Along with severe behavioral disturbances
What factors determine penetrance in Huntington’s disease?
- Age-dependent penetrance
- Age of onset depends on degree of expansion
- adult onset: CAG repeats 36-55
- juvenile onset: CAG repeats > 60
- Greater expansion through spermatogenesis
- Triplet repeat-dependent penetrance
Describe the CAG repeat expansion (pathogenesis)
- Expanded N-terminal polyglutamine tract interferes with/change the function of the protein
- GAIN OF FUNCTION mechanism
- Knock-out htt mice do NOT have HD
- People with deletion 4p region do NOT have HD
Describe the polyglutamine protein and its interactors
Mutant has altered protein conformation leading to protein accumulation and aberrant interactions
- HD is truly a mutlisystem disorder (think: heart transplant story)
What is Myotonic Dystrophy I (DMI)?
- What are the clinical finding phenotypes
Multisystem disorder
- Skeletal and smooth muscle
- Eye, heart, endocrine and CNS
Clinical findings categorized into 3 phenotypes:
- Mild
- Classic
- Congenital
Describe the different phenotypes of DMI
Mild DM1:
- Cataract and mild myotonia
- Life span is normal
Classic DM1:
- Muscle weakness and wasting
- Myotonia
- Cataract
- Cardiac conduction abnormalities
- Adults may become physically disabled
- May have a shortened life span
Congenital DM1:
- Hypotonia and severe generalized weakness at birth
- Often with respiratory insufficiency and early death
- Mental retardation is common
What determines the symptomatology in Myotonic Dystrophy I?
Repeat length
Greater expansion occurs when with Myotonic Dystrophy?
Greater expansion through oogenesis
How to test Myotonic Dystrophy?
- Slower relaxation after contraction (won’t be able to tell with handshake; do hand-grip test)
- Percussion myotonia (with reflex hammer)
What are features of myopathic facies?
- Mouth downturned and open
- Ptosis
Describe the pathological effects of the expanded RNA in Myotonic Dystrophy
Pathogenic mechanism involves aberrant binding of expanded RNAs to RNA-binding proteins
- Affected proteins include: Insulin receptor, chloride channel, cardiac troponin, and others, thus causing a plethora of phenotypic abnormalities.
What is the most common inherited form of intellectual disability?
Fragile X Syndrome
What is the inheritance pattern for fragile X syndrome?
X linked
- Most persons with fragile X are male
What is seen here?
Fragile X region of chromosome
How is Fragile X diagnosed?
DNA analysis