Exam 2: Lecture 32

Question 1

Trinucleotide repeat disorders

Answer 1

• areas of the gene with repetitive sequence of 3 nucleotides
• expansion of the repeat causes problems
• contraction of the repeat can cause problems too
• can happen during oogenesis and spermatogenesis

Question 2

What are 3 mechanisms that can cause trinucleotide repeat disorders?

Answer 2

1) loss of function : leads to silencing of transcription
2) gain of function: alterations in protein structure
3) Gain of function: mediated by RNA

Question 3

Describe the nature and effects of CAG (encodes glutamine) repeats

Answer 3

• poly glutamine tracts tend to cause misfolded protiens that aggregate
• may suppress transcription of other genes, cause mito dysfunction. or trigger apoptosis
• large intranuclear inclusion (aggregated proteins)
• ex. –> huntington and spinocerebellar ataxia I
• tend to affect the neurological system

Question 4

What is Fragile X syndrome?

Answer 4

• common cause of intellectual disability
• affects males greater than females
• trinucleotide repeat expansion in the FMR1 gene
• chromosome looks pinched at the bottom on both

Question 5

Describe the full mutation of Fragile X clinical features (Males)

Answer 5

• neurologic: intellectual disability, epilepsy. and autism spectrum disorder, anxiety, ADHD, and aggressive behavior
• physical features: long face, everted ears, macro-orchidism (abnormally large testes), sometimes CT disorders

Question 6

Full mutation of Fragile X syndrome (Female) clinical features

Answer 6

• about half of some feature
• variable

Question 7

What is the pathophysiology of Fragile X syndrome in full mutation?

Answer 7

• entire 5’UTR to be abnormally methylated and it extends to the promotor region and causes transcriptional suppression
• FMR1 is a widely expressed cytoplasmic protein –> most abundant in the brain and testes
• controls a lot of processes, especially in brain processes

Question 8

Describe the features of Fragile X syndrome premutations

Answer 8

• repeats of 55-200 can cause 2 diseases
• Fragile X associated Tremor/ Ataxia syndrome
• males–> 50% with premutation develop this condition
• progressive neurodegenerative syndrome starting from 6th decade
• intention tremors, cerebellar ataxia–> leading to Parkinson’s
• female–> premature ovarian failure before 40 y/o (menopause and fertility issues)

Question 9

What is the pathophysiology of Fragile X syndrome prematutation?

Answer 9

• FMR1 is not methylated/silences
• continues to be transcribed and forms abnormal mRNA with expanded CGGs
• the mRNA are toxic and aggregates in the nucleus and form intranuclear inclusions in the CNS/PNS
• recruit RNA binding proteins , impairs their function by sequestration

Question 10

What is anticipation in Fragile X syndrome?

Answer 10

• repeat sizes can expand in mutogenesis (gametgenesis)
• they are unstable
• fragile X expands in maternal oogenesis
• may see worsening throughout generations

Question 11

Describe mitochondrial inheritance

Answer 11

• 37 genes encoded on mito genome
• 13 are a part of ETC; 22 tRNA, and 2 rRNA
• mito DNA mutations typically affect organs that are dependednt of oxidative phosphorylation
• CNS, skeletal muscle, heart, liver, and kidneys

Question 12

inheritance

Answer 12

• only egg cells can pass it on–> pedigree will appear to tranmit only through female s
• female carriers will affect all their children

Question 13

Describe mito DNA inheritance in association with heteroplasmy

Answer 13

• multiple copies of genome in each mitochondria and there are multiple mitochondria in each cell
• called heteroplasmy–> some mito may be mutated or normal; can be different distribution of mutated mito genome
• causes substantial variation of expression of mito disease between diff tissue
• also cause variation between family members
• some may have more expression and mutated amounts than others

Question 14

Mitochondrial disease

Answer 14

• any organ any symptom, any age
• common symptoms: myopathy, neurologic, cardia, vision/hearing problems

Question 15

LHON- Leber hereditary optic neuropathy

Answer 15

• painless vision loss in early adulthood (onset 2nd - 3rd decade)
• starts in one eye and then the other eye shortly after
• +/- other symptoms such as cardiac conduction defects, movement disorders, neurologic abnormalities
• genetics: 3 common pathogenic variants in mtDNA causes 90% of cases–> MT-ND1, MT-ND4, MT-ND6 ( founder effect French Canadians)
• reduced penetrance 50%-M and 90%-F LHON pathogenic variant do NOT develop blindness

Question 16

Leigh Syndrome

Answer 16

• Subacute necrotizing encephalomyelopathy
• progressive neurodegenerative disease that starts in infancy or early childhood
• attacks of developmental regression –> stop talking or losing the ability to walk
• recurrent attacks of psychomotor regression
  respiratory abnormalities
  ataxia, nystagmus, hypotonia
• optic atrophy
• brainstem and BG dysfunction
• can be due to mito genome or Mendelian (AR or X linked)
• will get an MRI is suspicious and genetic testing

Question 17

Aminogycoside toxicity

Answer 17

• mutations in certain genes can cause predisposition to hearing loss if exposed to aminoglycoside antobiotics
• MTRNR1 gene encoding the 12S rRNA –> occurrs within days or weeks of exposure
• is bilateral and severe-profound but not progressive
• aminoglycosides are often avoided in the NICU if possible
• can cause hearing loss later even without exposure

Question 18

Name aminoglycoside antibiotics: TANGS

Answer 18

• Tobramycin
• Amikacin
• Neomycin
• Gentamicin
• Streptomycin

Question 19

Describe Imprinting disorders

Answer 19

• genes are only transcriptionally active when transmitted by a certain sex
• homologous locus from other parent is inactive
• epigenetic modifications takes place during spermatogenesis or oogenesis that silences specific alleles
• could be on of off–> through methylation

Question 20

Chromosome 15

Answer 20

• causes several imprinting disorders
• repetitive DNA sequence (low copy DNA) on the long arm (q arm)
• due to this sometimes there misalignment that leads to duplication or deletion
• 5 common break points
• Imprinted region depends on maternal or paternal genetic material is affected; different disorder results
• ex. Prader- Willi syndrome and Angelman syndrome

Question 21

What are clinical features of Prader- Willi?

Answer 21

• hypotonia and difficulty feeding as infants
• never get the feeling of being full (hyperphagia)–> later childhood hyperphagia leading to obesity
• dysmorphic features
• short stature
• hypogonadism
• behavioral: autism. OCD, and manipulation
• almond shaped eyes
• developmental delay and cognitive impairment
• small hands and short fingers

Question 22

What happens in Prader Willi syndrome?

Answer 22

• missing paternal paternal part of chromosome 15
• could be due to low copy DNA repeats–> deletions
• uniparental disomy 15 (maternal); completely missing chromosome 15 from dad and both chromosome 15 are from mom (2)

Question 23

How does Uniparental disomy happen?

Answer 23

• trisomic rescue –> during meiosis trisomy resulted, one of daughter cells losses one chromosome 15, now its back at disomy
• you could lose one from mom or from dad –>could lead to 2 from mom

Question 24

AngelMan Syndrome clinical features

Answer 24

• microcephaly (significantly small head)
• ataxia
• characteristic happy disposition
• seizures
• sever developmental delay–> no or very little speech development
• autism
• hypopigmentation

Answer 25

- missing maternal part of chromosome 15 - low copy DNA repeats that leads to deletion - uniparental disomy of 15q (2 of dad chromosome 15) - mutation in UBE3A mutation

Question 26

Gonadal mosaicism

Answer 26

- when there is a pathogenic variant in gonadal tissue, NOT in the rest of the body - autosomal dominant disorder - parents are unaffected; assume it is de novo - if they pass it on to other children, it is gonadal mosaicism - we always say recurrence of 1% due to this phenomenon

Question 27

Beckwith- Wiedemann syndrome

Question 28

Russell- Silver syndrome

Question 29

Pseudohypoparathyroidism