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Medicine year 1 > Genetic diseases > Flashcards

Genetic diseases Flashcards

1
Q

Down’s syndrome

A

Clinical features: hypotonia, excess nuchal skin, septal defects, short stature, single palmar crease, low IQ but advanced social skills, flat nasal ridge, epicanthic folds

Mechanisms

  1. Aneuploidy: trisomy 21 during meiosis
  2. Robertsonian translocation: 2/3 de novo translocations
  3. Mosaicism: mitotic non-disjunction in ZYGOTE. Severity of disease depends on how early on the disjunction occurred. Doesn’t always manifest-depends on proportion of cells affected by aneuploidy (product of non-disjunction) This also ultimately leads to disomy/monosomy.
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2
Q

2 examples of autosomal aneuploidy

A
  1. Down’s syndrome: trisomy 21
  2. Patau syndrome: trisomy 13
    - heart defects
    - cleft lip/palate
    - mental retardation
  3. Edward’s syndrome: trisomy 18
    - heart defects
    - kidney malformation- HORSESHOE KIDNEY
    - digestive tract defects- intestine protrudes outside abdomen
    - mental retardation/developmental delay
    - microcephaly
    - cleft lip/palate
    - typical hand posture: clenched hands with overlapping fingers
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3
Q

2 examples of sex chromosome aneuploidies

A
  1. turner’s syndrome

2. Klienfelter’s syndrome

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4
Q

Turner’s

A

MONOSOMY X
-80% due to loss of X or Y chromosome in paternal meiosis
-other causes: RING CHROMOSOME, single arm deletion, mosaicism
-all patients are female
-generalised oedema+swelling in neck region
-low posterior hairline
-broad chest
-aorta defect in 15% of cases
-short stature
-webbed neck
-infertility
-sensorineural deafness and recurrent ear infections
-behavioural problems
-normal intelligence
Treatment: oestrogen repalcement for secondary sexual charactersitics and prevention of osteoporosis

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5
Q

Klinefelter’s

A

POLYSOMY X (47, XXY)

  • X chromosome from either mother or father
  • only males
  • clumsiness, verbal learning disability
  • taller than average, long lower limbs
  • 30% gynaecomastia
  • ALL INFERTILE
  • -narrow shoulders, wide hips (female traits)
  • loss of secondary sexual characteristics: reduced facial and pubic hair
  • higher risk of leg ulcers, osteoporosis, breast carcinoma in adulthood
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6
Q

What is a genomic disorder? 2 examples

A

A GENOMIC disorder is characterised by DELETIONS or DUPLICATIONS i.e. loss or gain of DNA

  1. Di george
  2. Charcot-Marie Tooth
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7
Q

Di george

A

DELETION syndrome
-microdeletion of 22q11.2 region containing TBRX1 gene that encodes a transcription factor important in numerous developmental processes

Clinical features

  • cardiac abnormalities - TETRALOGY OF FALLOT
  • hypoplastic thymus
  • hypocalcaemia
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8
Q

Charcot-marie-tooth disease type 1A

A

DUPLICATION syndrome
-microduplication of PMP22 (peripheral myelin protein 22) gene on Chr 17, which encodes for an INTEGRAL MEMBRANE PROTEIN that is a major component of myelin in peripheral nervous system

Diagnostic features
-muscle weakness
-missing reflexes
0foot defromities
-lack of sensation in hands and arms
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9
Q

Examples of monogenic disorders

A

Huntingtons, cystic fibrosis, haemophilia

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10
Q

Examples of complex genetic disorders

A

Type 2 diabetes, Schizophrenia, Crohn’s disease

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11
Q

Example of autosomal dominant disorder

A

Huntington’s disease

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12
Q

Huntington’s disease

A

-autosomal dominant

Mechanism

  1. HTT gene on chromosome 4, which encodes Huntingtin protein
  2. HD patient has one copy of MUTATED Huntingtin gene
  3. This encodes a TOXIC version of Huntingtin protein that forms CLUMPS
  4. Cell death in basal ganglia of brain–>symptoms

Molecular level

  • caused by repeats of unstable CAG (amino acid=GLUTAMINE)
  • the more repeats, the more severe the disease

GENETIC ANTICIPATION

  • age of onset DECREASES
  • severity of symptoms INCREASES
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13
Q

Example of autosomal recessive disorder

A

Cystic fibrosis

Features

  • chronic, life-threatening
  • thick mucus in lungs–>breathing problems, infections
  • blockages in pancreas–>affects digestive enzymes

Treatment=daily physiotherapy

Mechanism

  1. CFTR gene on chromosome 7 encodes a protein called cystic fibrosis transmembrane conductance regulator (CFTR)
  2. CF patients inherit TWO copies of mutated CFTR gene
  3. Absence of a functional CFTR protein affects CHLORIDE ION FUNCTION in epithelial cells
  4. Disruption of salt/water regulation causes THICK MUCUS –>symptoms

MOLECULAR LEVEL

  • Themost common mutation (ΔF508)results fromDELETIONofthree nucleotideswhich causes theloss ofphenylalanine(Phe)at the 508th position on the protein (thus it’s also a GENOMIC disorder)
  • deletion affects folding of CFTR protein and causes its breakdown in the ER before it can be transported to the membrane
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14
Q

Example of X-linked recessive disease

A

Haemophilia

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15
Q

Haemophilia

A
  • deficiency in individual clotting factors
  • patients bruise easily and bleed for longer
  • two types: A and B

Mechanism (A)

  1. F8 gene on Chromosome X encodes a protein called coagulation factor VII
  2. Boys with Haemophilia A inherit one copy of a MUTATED form of F8 gene
  3. LACK of functioning factor VII–>symptoms
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16
Q

Same gene, different mutation

A

Cystic fibrosis and Congenital Absence of the vas Deferens (CAVD) caused by mutation in CFTR gene

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17
Q

Same disease, different genes

A

Haemophiilia A caused by mutation in F8 gene on chromosome X
Haemophilia B caused by mutation in F9 gene on chromsome X- encodes different coagulation factor but results in same symptoms

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18
Q

Retinoblastoma

A

Retinoblastoma=tumour suppressor gene. Also a retinoblastoma protein.

Normally, retinoblastoma binds to E2F (a transcription factor), preventing its expression. Cyclin CDK phosphorylates retinoblastoma–>E2F free to go through the cell cycle.

BUT, in cancer, retinoblastoma (mutated form) can’t bind to E2F–>unregulated transcription and replication.

Two types:
1. Familial
Hit 1: Germline mutation in Rb gene
Hit 2: somatic mutation in Rb gene

  1. Sporadic
    Both hits=somatic mutations in SAME CELL
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19
Q

Chronic myeloid leukaemia

A

General features

  • clonal myeloproliferative disorder–>overproduction of ABNORMAL mature granulocytes (neutrophils)
  • disorder of haematological stem cells
  • three phases: chronic, accelerated, blast crisis (overproduction of blasts- precursors)
  • symtoms: LACK OF RBC (because bone marrow space mostly occupied by WBC synthesis), lack of platelets (again due to reduction in bone marrow space), lack of WBC so infections (bc the WBC overproduced are DEFECTIVE)

MECHANISM

  • philadelphia chromosome
  • translocation between ABL-1 gene in chromosome 9 and BCR gene in chromosome 22
  • fusion protein BCR-ABL1–>MUTATED TYROSINE KINASE (potent cell-signalling cascade activator) which results in uncontrolled cell division

Treatment

  • imatinib=TYROSINE KINASE INHIBITOR. Blocks ATP binding site of BCR-ABL1 protein.
  • though lots of people lose response to treatment
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20
Q

Acute myeloid leukaemia (AML)

A

Features

  • divided into FAB M0-M7
  • key histological feature=presence of AUER RODS

Mechanism

  • FAB M3/promyelocytic leukkaemia (APML)- DIC and haemorrhage (medical emergency)
  • abnormal accumulation of immature granulocytes called promyelocytes
  • Retinoic acid receptor alpha (RARa) on chromosome 17 and PML on chromosome 15—>fusion product PML-RARa
  • RARa=nuclear receptor bound by retinoic acid; regulator of DNA transcription
  • fusion product binds too strongly to DNA–>inhibits transcription of TSGs–>cancer

Treatment

  • all trans retinoic acid (ATRA): DISSOCIATES co-repressors- restoring normal transcription
  • doesn’t KILL cells so need continuous therapy as residual stem cells remain
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21
Q

Breast cancer genes

A

BRCA1
BRCA2

Both are TSGs

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22
Q

Pathogenetic mechanism of breast cancer

A

BRCA 1 and 2 are involved in DNA repair. Mutations occur anywhere along exons, but ultimately result in formation of incorrect protein which fails to correctly repair DNA–>impaired DNA repair (common theme in cancer)

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23
Q

Two types of colorectal cancer

A
  1. Familial adenomatous polyposis (FAP)
  2. Lynch syndrome (hereditary non-polyposis colorectal cancer)
  3. Peutz-Jegher
  4. Gardner
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24
Q

FAP

A
  • 1000s of polyps in colon, each one has a small chance of developing into cancer–>HIGH overall risk of cancer
  • mechanism: autosomal dominant mutation in APC gene in chromosome 5 (but also a recessive form)
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25
Q

Lynch syndrome

A

-autosomal dominant mutation in MLH1 or MSH2 (DNA mismatch repair genes)

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26
Q

2 main classes of MONOGENIC diabetes

A
  1. MODY- maturity onset diabetes of the young

2. PND- permanent neonatal diabetes

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27
Q

4 types of MODY

A
  1. HNF1-alpha
  2. Glucokinase
  3. HNF4-alpha
  4. HNF-1 beta (RCAD)
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28
Q

HNF1 alpha MODY

A
  • HNF1 alpha=gene that codes for a transcription factor responsible for stimulating insulin production
  • absence of TF–>less glycolysis–>less ATP produced–>less depolraisation through ATP-sensitive potassium channel (i.e. potassium allowed to LEAVE the cell)–>less insulin produced
  • Treatment=SULPHONYLUREAS. These bind to ATP-sensitive potassium channel, cause it to close–>depolarisation–>opening of calcium channel–>calcium influx–>normal insulin production as insulin released from granules
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29
Q

Glucokinase MODY

A
  • Glucokinase: hexokinase IV. Converts glucose to glucose 6 phosphate in liver and pancreas. Beta cell sensing enzyme.
  • triggers conversion from glucose to glucose 6 phosphate when blood glucose concentration exceeds 4mmol/l. In glucokinase MODY, this set-point is higher
  • patients operate at consistently higher levels of blood sugar (hyperglycaemia)–but doesn’t exert microvascular effects. So not really symptomatic or dangerous- in fact treatment with insulin is more dangerous because it causes compensatory mechanisms in patients e.g. increased adrenaline and cortisol.
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30
Q

HNF4-alpha MODY

A
  • similar to HNF1 alpha MODY but RARER
  • older age of onset
  • low renal glucose threshold
  • macrosomia: newborn significantly larger than average
  • transient neonatal HYPOglycaemia
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31
Q

HNF1-beta MODY

A
  • Renal cysts and diabetes (RCAD)
  • genital tract mutations
  • ->COMPLEX SYNDROME
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32
Q

PND

A
  • ATP production is normal, but mutation in ATP-sensitive potassium channel
  • many different mutations, each of which cause a change in different subunits of this channel
    e. g. KCNJ11 codes for Kir 6,2 subunit; ABCC8 codes for Sur 1 subunit
  • ultimately, mutations prevent channel from closing even in the presence of normal ATP–>less depolarisation–>less insulin secretion
  • treatment=SULPHONYLUREAS. Bind to Sur 1 subunit and restore normal function so channel closes in response to ATP production
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33
Q

Other genetic diabetes

A
  1. MITOCHONDRIAL DIABETES

2. Polygenic diabetes: requires 2 hits (Knuddson’s hypothesis)

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34
Q

Mitochondrial diabetes: 2 types

A
  1. Maternally inherited diabetes and deafness (MIDD)
  2. Myopathy, encephalopathy, lactic acidosis, stroke-like episodes (MELAS)

Heteroplasmy: humans have multiple copies of mitochondrial DNA in each cell, and different cells contain different numbers of mutated mitochondrial genomes. Makes diagnosis difficult.

35
Q

Mutations in HNF-1 alpha gene

Also, what is more common in obesity than diabetes?

A

Mutations

  1. Missense- single nucleotide changes
  2. Frameshift- insertions or deletions

Non-genetic CHROMOSOMAL changes (structural changes)

  1. Inversions
  2. Translocations (balanced)

ON THE OTHER HAND, COPY NUMBER VARIANTS (INSERTIONS OR DELETIONS OF ENTIRE REGIONS OF GENOME- AS OPPOSED TO FRAMESHIFT)

36
Q

2 examples of imprinting disorders

A
  1. Praeder-Willi: MATERNAL imprinting
  2. Angelman: PATERNAL imprinting

–>both are same REGION of chromosome 15, though not the same GENE (obvs)

37
Q

Symptoms of PWS vs Angelman

And clinical detection?

A

PWS

  • muscle hypotonia
  • hyperphagia (all consuming appetite)
  • obesity (type II diabetes)
  • mental retardation
  • short stature
  • small hands, feet
  • delayed/incomplete puberty
  • infertility

Angelman

  • severe developmental delay
  • poor or absent speech
  • gait ataxia
  • “happy demeanour”
  • microcephaly
  • seizures

Clinical detection: FISH, PCR

38
Q

Management of PWS vs Angelman

A

PWS

  • appetite inhibitors/diet restriction
  • exercises to increase muscle mass
  • growth hormone for short stature
  • hormone replacement at puberty

Angelman

  • anti-convulsant
  • physiotherapy
  • communication therapy -symptomatic treatments
39
Q

Genetic mechanism of PWS vs Angelman

A

PWS

  • PATERNAL defect
  • lack of functional paternal copy of PWS critical region on 15q11-q13

Angelman

  • MATERNAL defect
  • lack of functional maternal copy of PWS critical region on 15q11-13

BOTH
mostly due to DELETION, then UNIPARENTAL ISODISOMY, then POINT MUTATIONS and TRANSLOCATIONS

40
Q

2 examples of mitochondrial disorders

A
  1. MELAS- mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes
  2. LHON- Leber’s Hereditary Optic Neuropathy
41
Q

MELAS

A

Progressive neurodegenerative disorder

Symptoms:

  • muscle weakness
  • seizures
  • hemiparesis (Weakness on ONE side of body)
  • vomiting
  • DEMENTIA

Diagnosis: muscle biopsy
Treatment: symptomatic

Cause: single mutations in SEVERAL genes

  1. MTTL1- tRNA translates codon as PHENYLALANINE instead of LEUCINE during mitochondrial protein synthesis
  2. MTND1, MTND5- NADH dehydrogenase subunits 1 and 5
42
Q

LHON

A
  • degeneration of retinal ganglion cells
  • loss of sight, most become blind eventually
  • bilateral, painless, loss of central vision and optic atrophy
  • dysfunctional optic nerve mitochondria- optic nerve dies
  • more common in males

Diagnosis- blood test for mtDNA mutations

Cause (90%)

  • MTND1, MTND4,MTND5, MTND6- code for NADH dehydrogenase subunits 1,4,5,6
  • MTCYB: cytochrome b
43
Q

Two examples of inborn errors of metabolism currently included in UK neonatal screening programmes

A
  1. Phenylketonuria (PKU)

2. MCADD: medium chain acyl co-A dehydrogenase deficiency

44
Q

PKU

A

Features and symptoms

  • severe mental retardation and convulsions
  • blonde hair/blue eyes
  • eczema

Mechanism

  • deficiency in phenylalanine hydroxylase (enzyme that converts Phe to Tyr)
  • accumulation of Phe–>converted back to Phenylpyruvate- excreted in urine
  • Tyrosine deficiency-reduced melanin, accumulation of homogensitic acid–>alkaptonuria (brown discolouration of eyes and skin, progressive joint damage esp. spine)

Treatment

  • early detection
  • remove Phe from diet (and monitor levels)
  • protein supplements to supply other amino acids
  • strict diet in pregnancy
45
Q

MCADD

A
  • mutation in ACADM gene (85% A985G)
  • presents in infancy with
    1. Episodic hypoketotic hypoglycaemia (low blood glucose, no ketone bodies produced due to no fatty acid metabolism)
      2. Vomiting, coma, metabolic acidosis, encaphalopathy
      3. If undaignosed- 25% mortality first episode
  • inability to break down acyl-CoA–>no fatty acid metabolism
  • treatment: adequate calorie intake to avoid fatty acid oxidation (i.e. no fasting)
46
Q

3 ways of quantifying residual disease in CML

A
  1. Cytogenetic analysis (G banding) in first 6-12 months
  2. FISH: lok for fusion of different colours showing diff genes in fusion product. Higher resolution but need a diff method when disease drops to less than 1%.
  3. Minimal residual disease markers/ RTqPCR: amplify sample, quantify fusion product.
47
Q

3 examples of pharmacogenomic markers

A
  1. KRAS
  2. EGFR
  3. BCR-ABL1 T3151
48
Q

KRAS

A
  • test with cetuximab for colorectal cancer

- mutation means less likelihood of response

49
Q

EGFR

A
  • test with gefitinib for non-small cell lung cancer

- mutation means more likelihood of response

50
Q

BCR-ABL T3151

A
  • test with dasatinib for CML

- mutation means less likely to respond

51
Q

3 methods of inheriting down’s

A
  1. Trisomy 21
  2. Robertsonian translocation (balanced, but affects offspring)
  3. Mosaicism- non-disjunction during mitosis
52
Q

3 methods of PWS

A
  1. Deletion (most common)
  2. Uniparental isodisomy
  3. Imprinting disorder- mutation in imprinting region i.e. you have maternal and paternal chromosome but for some reason paternal copy becomes imprinted too
53
Q

3 methods of angelman

A
  1. Deletion (most common)
  2. Uniparental isodisomy: 2 copies of paternal chromosome so you lose maternal function
  3. Imprinting defect: in maternal chormosome, resulting in loss of function
  4. Point mutation at UBE3A: results in loss of function in maternal chromosome
54
Q

Burkitt’s lymphoma

A

t(8:14)

Gene product: cMYC-IgH

55
Q

CML

A

t(9:22)

Gene product: BCR-ABL1

56
Q

APML

A

t(15;17)

Gene product: RARA-PML

57
Q

Ewing’s sarcoma

A

t(11;12)

Gene product: FLI1-EWS

58
Q

Nuchal translucency timing

A

11-14 weeks (routine)

59
Q

Mid-trimester scan

A

20 weeks

60
Q

Soft marker for DS

A

Nasal bone- absent/small

61
Q

Importance of nasal bone scan

A

When taken along with NT and maternal age, nasal bone scan increases sensitivity of DS screening

62
Q

1st trimester maternal serum screening

A

Look for presence of

  1. HcG
  2. PAPP A: pregnancy associated plasma protein A
63
Q

2nd trimester maternal serum screening

A

Look for presence of

  1. HcG
  2. PAPP A
  3. Alpha feto protein
  4. uE3: oestriol
64
Q

Down’s syndrome 1st trimester tests

A
  1. NT: ELEVATED
  2. Beta-HcG: ELEVATED
  3. PAPP A: LOW
65
Q

Down’s syndrome 2nd trimester tests

A
  1. Oestriol: LOW
  2. AFP: LOW
  3. HcG (TOTAL): HIGH
66
Q

DS triple test

A

AFP, unconjugated oestriol, hCG+maternal age

67
Q

DS NT

A

NT+maternal age

68
Q

Quadruple test

A

AFP, unconjugated oestriol, hCG, inhibin A+age

69
Q

Combined test

A

EARLIEST, MOST ACCURATE

  1. NT
  2. free B-hCG
  3. PAPP-A
  4. Maternal age
70
Q

Integrated test

A
  1. NT
  2. PAPP-A in first trimester
  3. AFP
  4. free B-hCG
  5. Oestriol
  6. Inhibin A- second trimester
71
Q

cffDNA offered by NHS for?

A
  1. sex-linked conditions
  2. detecting sex (for disease purposes)
  3. rhesus typing
72
Q

Rhesus typing

A

if NEGATIVE then BAD

73
Q

CVS timing and risks

A

TIMING: 11-14 weeks (earlier than amniocentesis)

RISKS:

  1. Miscarriage (1-2% risk)
  2. rhesus sensitisation
  3. limb defects
74
Q

Amniocentesis timing and risks

A

TIMING: 16 weeks

COMPLICATIONS:

  1. Miscarriage (1%)
  2. Infection
  3. Rh sensitisation
  4. Liquor leakage (leakage of amniotic fluid)
  5. Late diagnosis
75
Q

Rh sensitization

A

All rhesus negative mothers get anti-D within 72h

76
Q

CffDNA detectable from?

A

9 weeks

77
Q

Tests done with DNA sample obtained from CVS and amniocentesis

A
  1. KARYOTYPING (if chromosome abnormality suspected). Results in 2 weeks
  2. QF-PCR: FOR EVERYONE. Trisomies, sex chromosomes if disorder suspected. Results in 1-2 days.
78
Q

2 stages of adoption

A
  1. Registration and checks

2. Assessment and approval (by adoption agency)

79
Q

PGD

A
  1. Stimulate ovaries to produce eggs
  2. COllect eggs
  3. Inesmination: either IVF or inject single sperm into each egg
  4. Fertilisation
  5. Embryo biopsy- see whcih embryos don’t have genetic condition/carriers
  6. Transfer max 2 embryos (which don’t have condition or are carriers)
  7. pregnancy test
80
Q

Conditions PGD is used for

A
  1. Translocation arriers
  2. HD disease
  3. DMD
  4. CF
81
Q

Thanatrophic dysplasia

A

Mutation of FGFR-3

82
Q

Uses of PGD

A
  1. Tissue typing- stem cells from umbilical cord to help sibling
  2. Diagnosis of early and late onset diseases (Tay Sachs- early; Huntingtons- Late)
  3. Diseases with incomplete penetrance- BRCA1/BRCA 2
83
Q

Pharmacogenomics- getting the DOSE right

A

6-mercapturine used to treat leukaemia, Crohn’s disease, ulcerative colitis

  • people who are heterozygous for mutation in thiopurine methyl transferase (TMPT) metabolise it slowly –>more side-effects
  • they need a lower dose
84
Q

Pharmacogenomics- getting the DRUG right

A

Insulin for MODY is not needed- can be given oral drug (sulphonylureas)

Medicine year 1 (3 decks)

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