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
- 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
What are the clinical features of Fragile X syndrome?
- 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)
T/F: Females can have Fragile X syndrome
True
- Females with an expanded CCG repeat can present with developmental delay, learning disability, autism, and/orintellectual disability
What is the triplet repeat involved in Fragile X syndrome?
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
What are the mechanisms of pathogenesis in Fragile X syndrome?
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
Describe the different conditions falling under the following pathogenic mechanisms:
- Loss of function
- Gain of function
- Altered RNA function
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
T/F: CMT can present in childhood
True
What is Rett syndrome?
- Incidence
- Age group
Progressive nuerological disorder in girls
- 1/10,000
- Only seen in kids
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
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
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
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
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
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)
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
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
The different types of SMA differ how?
- Age of onset
- Max muscular activity achieved
- Survivorship
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
What are the genetic causes behind the different types of SMA?
All caused by recessive mutations in SMN1
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
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
- 10% SMN2 transcripts are full length protein 0-5 copies!
- >/=3 copies of SMN2: correlated with milder phenotype
What is Tay-Sachs disease?
Neurodegenerative disease
- Infantile type: onset first few months
- Lysosomal storage disorder
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
Describe the lysosomal storage component of Tay-Sachs disease
- Hexosaminidase A deficiency
- Abnormal storage of GM2 gangliosides
- (sphingoglycolipids of cellular membranes
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
Describe the mechanism/pathogenesis of Tay-Sachs Disease
Deficiency of hexosaminidase A
- Accumulation of GM2 ganglioside in lysosomes
- Particularly brain and spinal cord
What is the inheritance pattern of Tay-Sachs disease?
Autosomal recessive
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))
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
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
