Monogenic diseases Flashcards
What is a monogenic disease
A disease caused by the mutation of a single gene
Examples of monogenic disease
Huntington’s disease
Cystic Fibrosis
Haemophilia
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
SON 50% = affected 50% = unaffected DAUGHTER 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
