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MCD - Genetics > Monogenic diseases > Flashcards

Monogenic diseases Flashcards

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1
Q

Why are pedigree diagrams important?

A
  • Identify genetic diseases in a family
  • Identify inheritance patterns
  • Aid in diagnosis
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2
Q

Identify the mendelian inheritance patterns

A
  • Autosomal dominant
  • Autosomal recessive
  • X linked dominant (rare)
  • X linked recessive
  • Mitochondrial
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3
Q

Explain the mechanism of an autosomal dominant condition

A

At least one parent is affected, transmitted/affected by M or F, vertical transmission
HUNTINGTON’S DISEASE
-Motor, cognitive + psychiatric dysfunction (hyperkinesia - muscle spasms)
-Survival = 15-18 yrs
-Cell death to basal ganglia
-Caused by instable CAG triplet repeats (27-35 risk for child, 35-40 sometimes, 40-120 affected)

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4
Q

Down generation

A

Age of onset decreases and severity increases

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5
Q

Provide an example for an autosomal recessive condition

A

No affected parent, affects/transmitted by M or F, usually no family history
Congenital absence of vas deferens (CAVD) = infertility
CYSTIC FIBROSIS
-Chromic and life threatening
-Mucus affecting lung function, blockages in pancreas
-Treatment = daily enzymes + physio
-Mutation in CFTR gene on Ch 7 (Disruption of NaCl/H2O regulation = thick mucus)

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6
Q

Provide an example of an X-Linked recessive condition

A

No affected parents, transmitted by carrier F and only M are affected
HAEMOPHILIA
-Easy bruising, heavy bleeding
-Haemophili A + B (rarer)
-A = mutation in F8 = Coagulation factor 8
-B = mutation in F9 = coagulation factor 9
-Treatment = clotting factor injections

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7
Q

Incomplete penetrance

A

Symptoms are not always present in someone with a disease causing mutation

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8
Q

Variable expressivity

A

Disease severity may vary between people with the same disease causing mutation

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9
Q

Phenocopy

A

Having the same disease but with a different underlying cause

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10
Q

Epistasis

A

Interaction between disease gene mutations and other modifier genes can affect phenotype

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11
Q

Genetic Heterogeneity: Same gene, different mutations, different symptoms

A

CF and CAVD are both caused by mutations in the CFTR gene

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12
Q

Genetic Heterogeneity: Same disease, different genes

A

Haemophilia A + B

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13
Q

Genetic Heterogeneity: Same disease, different genes, different inheritance patterns

A

Epidermolysis bullosa can be autosomal dominant or autosomal recessive

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14
Q

Explain the mechanisms of dominance and treatments

A

-Mutation causes a production in a toxic protein
-Effects of the mutated gene masks the normal copy (Huntingtins)
TREATMENT = neutralise toxic protein or switch off mutant gene

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15
Q

Explain the mechanism of recessive conditions and its treatments

A

-Caused by absence of normal functional protein (CF and Haemophilia) TREATMENT = restore activity of missing protein by replacing the gene/products/affected tissue

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16
Q

Explain the mechanism of codominance

A

-Effects of both mutated and normal genes are present (Sickle cell trait)

17
Q

Outline the differences between monogenic and complex disorders

A

Monogenic

  • clear inheritance
  • No environmental influence
  • Rare
  • HD, CF, haemophilia

Complex Disorders

  • No clear inheritance
  • Environment is essential
  • Common
  • Type II Diabetes, schizophrenia, crohn’s disease
18
Q

Mutation vs Polymorphism

A 
Mutation = any heritable change in the DNA sequence
Polymorphism = a mutation at a >1% frequency in a population, can contribute to complex diseases
19
Q

What are the types of mutations?

A 
Missense = (Point mutation) codon changes, different amino acid
Nonsense = (Point mutation) ends prematurely due to stop codon
Insertion = (Frame-shift mutation) extra code will shift code
Deletion = (Frame-shift mutation) deletion of a base
20
Q

Explain the mechanism of Huntington’s disease

A
  • Inherit a mutated form of HTT gene on Chr 4
  • encode a toxic form of huntingtin = form clumps
  • Cell death in basal ganglia of the brain
21
Q

Explain the mechanism of Cystic Fibrosis

A
  • CFTR gene on Ch7 = CF transmembrane conductance regulator (2 copies of mutated gene)
  • x functional CFTR gene affects cl- function in epithelial cells
  • disrupt salt/water regulation = thick mucus
  • deletion affects folding of protein = affects movement
22
Q

Uniparental (iso)disomy

A

Receives 2 copies of a chromosome, or part of a chromosome from 1 parent and none from the other

  • caused by non-disjunction in meiosis II
    e. g. Prader Willi syndrome, Angelman syndrome
23
Q

Genomic Imprinting

A

In some cases 1 of the 2 chromosomes are turned on. The chromosome that is active is dependent on the parent of origin

24
Q

Chr 15 imprinting disorders

Prader - Willi syndrome (loss of paternal)

A 
SYMPTOMS: 
-hyperphagia = obesity
-mental impairment
-behavioural problems
-Muscle hypotonia 
-Short stature, small hands and feet
-Delayed/incomplete puberty, infertility
MANAGEMENT:
-Obesity = diest restriction
-exercise = ↑ muscle mass
-GH for short stature
-hormone replacement at puberty
25
Q 
Chr 15 imprinting disorders
Angelman syndrome (loss of maternal)
A

SYMPTOMS:
-developmental delay + speech impairment
-movement disorder (ataxia, tremulous limb movement)
-behavioural uniqueness (happy demeanours, excitable, short attention span
-microcephaly
-seizures (<3yrs onset)
MANAGEMENT:
-symptomatic - anticonvulsant physio, communication therapy
-normal life span

26
Q

What is the genetic mechanism of Prader-Willi Syndrome

A
  • Lack of functional paternal copy of the PWS critical region on 15q11-q13
  • 70% = deletion of critical region
  • 25% = two maternal copies (uniparental isodisomy)
  • 5% = translocations
27
Q

Heteroplasmy

A 
Within a single cell, there is a mixture of mutant and normal DNA containing mitochondria
0-3 affected mitochondria = No disease
5 = mild
9 = severe
causes variation in phenotype
28
Q

Mitochondrial inheritance

A

(GENOME) 37 genes, 2-10 copies per mitochondrion, 2-2500 mitochondria per cell

  • Affects both males and females
  • transmitted through females via oocytes
29
Q

mitochondrial disorder example: MELAS

A

Mitochondrial Encephalopathy Lactic Acidosis and Stroke-like episodes (Affects muscles and brain = ↑ mitochondria)
Progressive, muscle weakness, vomiting, episodic seizures, dementia, hemiparesis
Diagnosis: muscle biopsy
Treatment: symptomatic
Genetics: single mutations in multiple genes
>MTTL1 - tRNA translates phenylalanine instead of leucine
>MTND1/5 - NADH Dehydrogenase subunits 1 and 5

30
Q

mitochondrial disorder example: LHON

A

Leber’s Hereditary Optic Neuropathy
common in males
Bilateral, painless, loss of central vision. Optic atrophy (death of retinal ganglion cell axon) = eventual blindness
Diagnosis: Blood test fot mtDNA mutations, ophthalmological findings
Genetics: 90% of mutation in
>MTND1/4/5/6 - NADH dehydrogenase subunits
>MTCYB - cytochrome B

31
Q

UK Newborn Screening programme

A

-Physical exam
-Hearing test
-Blood spot test for genetic diseases
>PKU = Phenylketonuria
>Congenital hypothyroidism
>SCD
>CF
>MCADD = Medium chain acyl-coA Dehydrogenase Deficiency
»Homocystinuria
»Maple Syrup Urine Disease (branded-chain ketoaciduria)
»Glutaric Aciduria type 1
»Isovaleric Acidaemia

32
Q

Inborn error in metabolism

A

more than 200 diseases known
mostly autosomal recessive or x linked
defective proteins are mainly enzymes

33
Q

Inborn error in metabolism = Phenylketonuria

A

-Blonde hair, blue eyes, Eczema, (tyrosine deficiency = ↓ melanin)
-Phenylalanine hydroxylase deficiency
-Phenylalanine accumulates, converted to phenylpyruvic acid = excreted in urine
TREATMENT:
-early detection (no convulsions)
-screen for elevated levels of phenylalanine in blood ( remove from diet)
UNTREATED = seizure + mental difficulties

34
Q

Inborn error in metabolism = MCADD deficiency

A

Medium-Chain Acyl-CoA Dehydrogenase
-Most common disorder of fatty acid oxidation
-Mutation in ACADM gene
-episodic hypoketotic hypoglycaemia
-vomiting, coma, metabolic acidosis, encephalopathy
-25% mortality of 1st episode
MANAGEMENT:
-maintenance of calorie intake to prevent fatty acid oxidation
-avoid fasting, more than 12 hrs
-nutritional supplements with increased stress

35
Q

What are the types of obesity?

A
  • Syndromic = accompanied by mental difficulties and dysmorphic or clinical features (Prader Willi syndrome)
  • Monogenic = dominant (MC4R) or recessive (PCSK1, MRAP2, POMC) single gene disorders, leptin
  • common (in general population)
36
Q

Monogenic leptin deficiency

A 
Hunger
obesity
no puberty
poor growth
low thyroid
immune problems
37
Q

What is leptin?

A
  • Hormone made by adipocytes in white adipose tissue
  • proportionate to amount of adipose tissue
  • acts on hypothalamus (arcuate nucleus) = inhibits appetite
  • LOW = LOW body fat
  • HIGH = HIGH body fat

MCD - Genetics (6 decks)

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