Neurogenetic Disorders in Pediatrics Flashcards
1
Q
What are nucleotide repeat disorders?
A
- Dynamic Mutations
- Developmental and degenerative disorders caused by expansion of unstable repeats
- (These disorders can present in childhood or even infancy)
2
Q
What are examples of nucleotide repeat disordes?
A
- Huntington
- Myotonic dystrophy
- FMRI
3
Q
Where is the Huntington gene located?
- What is the triplet repeat?
A
- Mapped to 4p
- CAG repeat
4
Q
Describe Huntington disease
- Symptoms
- Age group
- Disease course
- Inheritance pattern
- Penetrance pattern
A
- 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
5
Q
Describe juvenile Huntington Disease
- Onset of symptoms
- What percentage of HD in US
- Childhood vs. teenagers
A
- Onset of symptoms
- 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
6
Q
What factors determine penetrance in Huntington’s disease?
A
- 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
7
Q
Describe the CAG repeat expansion (pathogenesis)
A
- 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
8
Q
Describe the polyglutamine protein and its interactors
A
Mutant has altered protein conformation leading to protein accumulation and aberrant interactions
- HD is truly a mutlisystem disorder (think: heart transplant story)
9
Q
What is Myotonic Dystrophy I (DMI)?
- What are the clinical finding phenotypes
A
Multisystem disorder
- Skeletal and smooth muscle
- Eye, heart, endocrine and CNS
Clinical findings categorized into 3 phenotypes:
- Mild
- Classic
- Congenital
10
Q
Describe the different phenotypes of DMI
A
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
11
Q
What determines the symptomatology in Myotonic Dystrophy I?
A
Repeat length
12
Q
Greater expansion occurs when with Myotonic Dystrophy?
A
Greater expansion through oogenesis
13
Q
How to test Myotonic Dystrophy?
A
- Slower relaxation after contraction (won’t be able to tell with handshake; do hand-grip test)
- Percussion myotonia (with reflex hammer)
14
Q
What are features of myopathic facies?
A
- Mouth downturned and open
- Ptosis
15
Q
Describe the pathological effects of the expanded RNA in Myotonic Dystrophy
A
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.
16
Q
What is the most common inherited form of intellectual disability?
A
Fragile X Syndrome
17
Q
What is the inheritance pattern for fragile X syndrome?
A
X linked
- Most persons with fragile X are male
18
Q
What is seen here?
A
Fragile X region of chromosome
19
Q
How is Fragile X diagnosed?
A
DNA analysis
20
Q
What are the clinical features of Fragile X syndrome?
A
- Hypotonia
- Developmental delay
- Intellectual disability
- Autism
- Should consider Fragile X in kids presenting (only) with autism
- Relative macrocephaly
- Within normal curve, but a little high
- Large ears
- Long face
- Prominent forehead
- Prognathia (typ post-puberty)
- Post-pubertal macroorchidism (big testes)
21
Q
T/F: Females can have Fragile X syndrome
A
True
- Females with an expanded CCG repeat can present with developmental delay, learning disability, autism, and/orintellectual disability
22
Q
What is the triplet repeat involved in Fragile X syndrome?
A
CGG
- CGG expansion in the 5’UTR of FMR1
Repeat length significance (don’t need to memorize):
- Normal, stable repeat: 5-44
- Mutable, indeterminant: 45-54
- Mutable, premutation: 55-200
- Mutable, full mutation: > 200
- Fragile X tremor ataxia: premutation: 55-200
- Primary ovarian insufficiency: premutation: 55-200
23
Q
What are the mechanisms of pathogenesis in Fragile X syndrome?
A
FMR1 encodes FMRP
Repeats that contain >200 copies (full mutation)
- Hypermethylation of FMR1
- Absence of mRNA
- Loss of FMRP expression
Abnormal dendritic spine morphology
- In patients with FRAXA
- Suggests that FMRP has role in
- Synaptic maturation and pruning
24
Q
Describe the different conditions falling under the following pathogenic mechanisms:
- Loss of function
- Gain of function
- Altered RNA function
A
Loss of function:
- FRAXA—transcriptional silencing
- Hypermethylation
- No RNA produced
Gain of function:
- HD: polyglutamine disorders, CAG altered protein function
Altered RNA function:
- DM1 (CTG or CCTG; noncoding)
- FXTAS (premuation alleles in FRAXA): berrant binding of expanded RNAs to RNA-binding proteins, with subsequent dysregulation of protein function
25
**T/F**: CMT can present in childhood
True
26
What is Rett syndrome?
- Incidence
- Age group
Progressive nuerological disorder in girls
- 1/10,000
- Only seen in kids
27
What are symptoms/signs of Rett syndrome? (neurological symptoms)
- Normal birth
- Normal early development
- Regression starting at ~18 months
- Loss of purposeful hand movements
- Acquired microcephaly
- Dystonia, spasticity, seizures
28
Describe Classical Rett Syndrome in terms of non-neurological systems
- Profound psychomotor retardation
* Episodic apnea / hyperpnea
* Ataxia
* Language impairment
* Panic-like attacks
- Gastrointesinal dysmotility
- Gallbladder dysfunction
- EKG abnormalities—prolonged QT
- Sleep disturbances
- Failure to thrive
- Osteoporosis
29
What mutation/genetics are involved in Classic Rett syndrome?
- Describe the pathogenesis
Mutation in **MECP2** on Xq28
- Binds specifically to methylated DNA and normally can act as a transcriptional repressor or a transcriptional activator.
- Effect is **epigenetic**
* Relates to the transcription of other genes which themselves do not harbor mutations!
* MeCP2 normally binds promoter and causes silencing of transcription; if it is abnormal, the transcriptions can go awry
- Expressed mostly in brain—involved in development and CNS patterning… and perhaps in pathogenesis of drug addiction
30
What are some MECP2 related disorders?
- Males vs. females
Other phenotypes in males and females
- **Females**: include classic Rett syndrome, variant Rett syndrome, and mild learning disabilities
- **Males**: severe neonatal encephalopathy and manic-depressive psychosis, pyramidal signs, parkinsonian, macro-orchidism (PPM-X) syndrome
- **Families**: X-linked intellectual disability
31
What is Spinal Muscular Atrophy (SMA)?
- Pathogenesis
- Symptoms
- Prognosis
- Inheritance pattern
- Gene involved
Group of neuromuscular disorders
- Degeneration and loss of anterior horn cells in the spinal cord, brainstem
* Anterior horn directs motor neurons; innervate contractile fibers in skeletal muscle
- Degeneration of cranial nuclei
- Symmetrical and proximal muscle weakness and atrophy
- Progressive
- **Autosomal recessive** inheritance
- **SMN1**
32
What is seen here?
SMA- spinal muscular atrophy
- Seen here is group atrophy (really pathognomonic for SMA)
- Round atrophic fibers and clumps of hypertrophic fibers
- (Left is normal skeletal muscle)
33
What is SMA Type I?
- Onset
- Symptoms
- Course of disease
**Werdnig-Hoffman**
- Onset **0-6 mo** (+/- decreased fetal mvt)
_Symptoms:_
- Hypotonia and Muscle weakness (frog leg posture)
- Lack of motor development
- Never achieves ability to sit without support
- Facial weakness: minimal or absent
- Fasciculation of the tongue: seen in most (XII)
- Absence of tendon reflexes\* (disturbed reflex arc)
- Paradoxical breathing—diaphragm involved late
- No sensory loss
- Alert appearance
- Normal cerebral function including cognition
**Progressive**
34
What is the clinical course of SMA?
- SMA is a progressive disorder
- More severe forms progress more rapidly
- SMA I: fatal by 2 years w/o intervention
* 50% mortality by 7 months
* 80% mortality by 12 months
- Longer survival if mechanically ventilated
35
The different types of SMA differ how?
- Age of onset
- Max muscular activity achieved
- Survivorship
36
Describe the different types of SMA
- **Type 0**: prenatal onset, joint contractures, facial diplegia, respiratory failure
- **Type I**: severe infantile Werdnig-Hoffman
- **Type II:** infantile chronic SMA
- **Type III**: juvenile, Wohlfart-Kugelberg-Welander
- **Type IV**: adult-onset
37
What are the genetic causes behind the different types of SMA?
**All** caused by **recessive** mutations in **SMN1**
38
Describe the genetics of the SMN1 gene (behind SMA)
- Pathophysiology
- Therapy
\*\*SMN1 gene is the one where (if deleted on both alleles) contributes to SMA\*\*
**SMN1: Survival Motor Neuron**
- Encodes for full-length SMN protein (FL-SMN)
- ~95-98% of individuals with SMA lack exon 7 in both copies
- ~2-5% of individuals are compound heterozygous for deletion of exon 7 and intragenic mutation
39
Describe the genetics of the SMN2 gene (behind SMA)
- Pathophysiology
- Therapy
SMN2 is the pseudo-gene; sits right next to SMN1; but even though pseudo-gene, 10% of the transcripts are full-length gene
- **Thus, more copies of this means less severe and later onset**
**SMN2: centromeric copy**
Don't need to memorize:
- Differs from SMN1 by 5bp, including a
- C→T transition within an AG rich exonic splicing enhancer
- Responsible for alternative splicing of exon 7
- 90% SMN2 transcripts is aberrantly spliced (SMN2Δ7 )
- Unstable protein; degraded
- 1**0% SMN2 transcripts are full length protein 0-5 copies!**
- \>/=3 copies of SMN2: correlated with milder phenotype
40
What is Tay-Sachs disease?
Neurodegenerative disease
- Infantile type: onset first few months
- Lysosomal storage disorder
41
Describe the infantile type of Tay-Sachs disease
Onset in first few months
- Normal at birth
- Progressive deterioration
- Death by 2-4 years
_Symptoms_
- Hypotonia and loss of milestones 3-6 mo
- Exaggerated startle rxn to loud noise
- Progressive neurological deterioration
- Seizures
- Visual impairment -\> blindnes
- Pathology restricted to nervous system
- No hepatosplenomegaly
42
Describe the lysosomal storage component of Tay-Sachs disease
- Hexosaminidase A deficiency
- Abnormal storage of GM2 gangliosides
- (sphingoglycolipids of cellular membranes
43
What is seen here?
Retina in Tay-Sachs disease
- Cherry red spot on fovea of macula (normal; only normal part of the eye)
- Red is NORMAL here; the surrounding retina has stored GM1 ganglioside in the ganglian cells
44
Describe the mechanism/pathogenesis of Tay-Sachs Disease
Deficiency of hexosaminidase A
- Accumulation of GM2 ganglioside in lysosomes
- Particularly brain and spinal cord
45
What is the inheritance pattern of Tay-Sachs disease?
Autosomal recessive
46
What is the epidemiology of Tay-Sachs
- Ashkenazic Jews; French Canadians of the eastern St. Lawrence River Valley area of Quebec; Cajuns from Louisiana; Old Order Amish in Pennsylvania (1/30 carrier)
- Panethnic (1/250 carrier))
47
How to test for Tay-Sachs?
- Analyte testing of HEX A activity
- Genetic testing of HEXA
* Carrier screening
* Targeted mutation analysis
* Del/dup analysis if Fr Canadian
* Sequence analysis
48
Describe how the Hexominidase A deficiency plays a part in the different onset types of Tay-Sachs
- Juvenile
- Chronic/Adult onset
- The level of the residual activity of the HEX A enzyme correlates inversely with the severity of the disease.
- Genotype-Phenotype correlation
