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Flashcards in Monogenic diseases Deck (36):

What is a monogenic disease

A disease caused by the mutation of a single gene


Examples of monogenic disease

Huntington's disease
Cystic Fibrosis


Reasons for taking a genetic family history

- Identify genetic disease in a family
- Identify inheritance patterns
- Aid diagnosis
- Assist in management of the condition
- Identify relatives at risk of disease


Process of building a pedigree diagram for family genetic history

- Start from the 'bottom' with affected child and siblings
- Record names, dates of birth
- Choose one parent, ask about their siblings, children and parents
- Record names, dates of birth, maiden names
- Ask for miscarriages, stillbirths or deaths in each partnership
- Ask about children through other partnerships


Labels for pedigree diagrams

Square = male
Circle = female
Diamond = sex unspecified
Empty symbol = unaffected
Filled-in symbol = affected
Arrow to symbol = person providing info
Diagonal line through symbol = deceased
Multiple individuals = put number of individuals inside symbol


Features and causes of Huntington's disease

- Autosomal dominant
- Motor, cognitive, psychiatric dysfunction
- Hyperkinesia = excess uncontrollable movement
- HTT gene on chromosome 4 encodes huntingtin protein
- Mutated gene encodes toxic form of protein that forms 'clumps'
- Cell death in basal ganglia of brain
- Mutation caused by unstable CAG triplet repeat, increasing number of repeats increases chance and severity of the disease


Explain dominant anticipation in the context of autosomal dominant diseases

Conditions such as Huntington's and myotonic dystrophy display a phenomenon where through out generations, the age of onset decreases and the severity increases. Can be due to an expansible, unstable triplet repeat
- Example is the CAG triplet repeat in Huntington's where the repeat becomes longer and longer throughout generations resulting in more severe presentation of the disease.


Summarise cystic fibrosis

- Autosomal recessive condition
- Patients inherit two copies of faulty CFTR gene
- Absence of functional CFTR leads to chloride ion channel dysfunction
- Failure of water/salt regulation
- Thick mucus
- Breathing problems
- Repeated infections


Transmission of autosomal dominant diseases

- At least one affected parent
- Transmitted by M or F
- Both genders affected
- Vertical transmission


Children chances of being affected, unaffected, or a carrier of autosomal dominant diseases

50% = affected
50% = unaffected


Transmission of autosomal recessive diseases

- No affected parent, both must be carriers
- Transmitted by M or F
- M and F affected
- Usually no family history


Children chances of being affected, unaffected, or a carrier of autosomal recessive diseases

25% = affected
50% = carriers
25% = unaffected


Transmission of X-linked disorders

- No affected parents
- Transmitted by carrier F
- Only M affected


Children chances of being affected, unaffected or a carrier of X-linked diseases

50% = affected
50% = unaffected
50% = carrier
50% = unaffected


Summarise features and causes of haemophilia

- X-linked disorder
- Patients bruise easily and bleed for longer
- Two types = A and B
- Boys with haemophilia A inherit mutated copy of F8, no functioning Factor VIII.
- Boys with haemophilia B inherit mutated copy of F9, no functioning Factor IX.


Main features and treatment of dominant conditions

- Usually caused by gene mutations that result in production of toxic protein
- Effects of mutated gene 'mask' normal copy when individual is heterozygous
- Treatment either counters the effects, neutralises the toxic protein, or switches off mutant gene


Main features and treatment of recessive conditions

- Usually caused by absence of working protein
- Effects of mutated gene only seen when normal copy absent (homozygous)
- Treatment needs to restore activity of missing protein by replacing the gene, the protein itself, or affected tissues


What are co-dominant conditions

- Both normal and mutated genes have equal dominance
- Effects of both mutated and normal genes apparent in people with both genes


What factors are included in a risk assessment calculation?

Chances of family members being carriers, chances of children being affected/unaffected/carriers, fraction of general population who random experience the disease or is a carrier


Two inborn errors of metabolism screened for neonatally

Phenylketonuria (PKU)
MCAD deficiency


Symptoms of phenylketonuria

- Blond hair/blue eyes (lack of melanin)
- Eczema, musty odour (excess phenylacetate)
- Seizures, severe mental retardation (if untreated)


Treatments of phenylketonuria

- Newborn screening
- Removal of phenylalanine from diet
- Protein supplements to supply other AAs
- Strict diet in pregnancy


What is MCAD deficiency and what are its causes?

- Medium-Chain Acyl-CoA Dehydrogenase deficiency
- Caused by a mutation in ACADM gene


Symptoms of MCAD deficiency

- Episodic hypoketotic hypoglycaemia (no ketone bodies produced, low blood glucose)
- Vomiting
- Coma
- Metabolic acidosis
- Encephalopathy
- 25% mortality in first episode if undiagnosed


Treatment of MCAD deficiency

- Avoid fasting
- Nutritional supplements at times of increased stress


Epigenetics definition

The study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA (study of heritable changes that occur outside laws of Mendelian inheritance)


Genetic imprinting definition

Genes expressed differently specific to their parent of origin


Examples of genetic imprinting disorders

Prader-Willi syndrome
Angelman syndrome


Prader-Willi syndrome clinical features

- Hyperphagia
- Obesity (from hyperphagia)
- Behavioural problems
- Muscle hypotonia
- Short stature, small hands and feet
- Delayed/incomplete puberty, infertility


Angelman syndrome clinical features

- Development delay
- Speech impairment
- Movement disorder
- Behavioural uniqueness; happy demeanour, excitable, short attention span
- Microcephaly
- Seizures, onset usually <3 years of age


Genetic mechanisms behind PW and Angelman syndromes

- De novo deletion
- Uniparental disomy
- Imprinting defect
- UBE3A mutation


Two examples of mitochondrial disorders

MELAS - Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like episodes
LHON - Leber's Hereditary Optic Neuropathy


Transmission of mitochondrial disorders

- Transmitted through females via oocyte
- Passed on to all children regardless of gender
- Phenotype can be variable due to heteroplasmy


Heteroplasmy definition

The presence of a mixture of mutated and normal mitochondria in a cell


Explain consequences of heteroplasmy on presentation of mitochondrial disorders

No mutated, all normal = no visible disease
Few mutated, all normal = no visible disease
Half mutated, half normal = no/mild disease
More mutated than normal = visible disease
Disease severity increases with mutated mitochondria presence


List defects in the leptin-melanocortin pathway leading to three forms of monogenic obseity

- Leptin deficiency
- Leptin receptor deficiency
- Pro-opiomelanocortin gene deficiency
- PC1 mutation
- MC4R mutation