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x_NeuroGenetics Review > Neurogenetic Disorders in Pediatrics > Flashcards

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)
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2
Q

What are examples of nucleotide repeat disordes?

A
  • Huntington
  • Myotonic dystrophy
  • FMRI
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3
Q

Where is the Huntington gene located?

  • What is the triplet repeat?
A
  • Mapped to 4p
  • CAG repeat
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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
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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
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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
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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
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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)
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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
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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
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11
Q

What determines the symptomatology in Myotonic Dystrophy I?

A

Repeat length

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12
Q

Greater expansion occurs when with Myotonic Dystrophy?

A

Greater expansion through oogenesis

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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)
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14
Q

What are features of myopathic facies?

A
  • Mouth downturned and open
  • Ptosis
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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.
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16
Q

What is the most common inherited form of intellectual disability?

A

Fragile X Syndrome

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17
Q

What is the inheritance pattern for fragile X syndrome?

A

X linked

  • Most persons with fragile X are male
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18
Q

What is seen here?

A

Fragile X region of chromosome

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19
Q

How is Fragile X diagnosed?

A

DNA analysis

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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
Q

T/F: CMT can present in childhood

A

True

26
Q

What is Rett syndrome?

  • Incidence
  • Age group
A

Progressive nuerological disorder in girls

  • 1/10,000
  • Only seen in kids
27
Q

What are symptoms/signs of Rett syndrome? (neurological symptoms)

A
  • Normal birth
  • Normal early development
  • Regression starting at ~18 months
  • Loss of purposeful hand movements
  • Acquired microcephaly
  • Dystonia, spasticity, seizures
28
Q

Describe Classical Rett Syndrome in terms of non-neurological systems

A
  • 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
Q

What mutation/genetics are involved in Classic Rett syndrome?

  • Describe the pathogenesis
A

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
Q

What are some MECP2 related disorders?

  • Males vs. females
A

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
Q

What is Spinal Muscular Atrophy (SMA)?

  • Pathogenesis
  • Symptoms
  • Prognosis
  • Inheritance pattern
  • Gene involved
A

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
Q

What is seen here?

A

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
Q

What is SMA Type I?

  • Onset
  • Symptoms
  • Course of disease
A

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
Q

What is the clinical course of SMA?

A
  • 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
Q

The different types of SMA differ how?

A
  • Age of onset
  • Max muscular activity achieved
  • Survivorship
36
Q

Describe the different types of SMA

A
  • 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
Q

What are the genetic causes behind the different types of SMA?

A

All caused by recessive mutations in SMN1

38
Q

Describe the genetics of the SMN1 gene (behind SMA)

  • Pathophysiology
  • Therapy
A

**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
Q

Describe the genetics of the SMN2 gene (behind SMA)

  • Pathophysiology
  • Therapy
A

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
40
Q

What is Tay-Sachs disease?

A

Neurodegenerative disease

  • Infantile type: onset first few months
  • Lysosomal storage disorder
41
Q

Describe the infantile type of Tay-Sachs disease

A

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
Q

Describe the lysosomal storage component of Tay-Sachs disease

A
  • Hexosaminidase A deficiency
  • Abnormal storage of GM2 gangliosides
  • (sphingoglycolipids of cellular membranes
43
Q

What is seen here?

A

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
Q

Describe the mechanism/pathogenesis of Tay-Sachs Disease

A

Deficiency of hexosaminidase A

  • Accumulation of GM2 ganglioside in lysosomes
  • Particularly brain and spinal cord
45
Q

What is the inheritance pattern of Tay-Sachs disease?

A

Autosomal recessive

46
Q

What is the epidemiology of Tay-Sachs

A
  • 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
Q

How to test for Tay-Sachs?

A
  • Analyte testing of HEX A activity
  • Genetic testing of HEXA
  • Carrier screening
  • Targeted mutation analysis
  • Del/dup analysis if Fr Canadian
  • Sequence analysis
48
Q

Describe how the Hexominidase A deficiency plays a part in the different onset types of Tay-Sachs

A
  • 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

x_NeuroGenetics Review (38 decks)

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