Monogenic diseases Flashcards
Segregation analysis; Modes of inheritance; Risk assessment; Genetic sceening; Epigenetics and genomic imprinting; Mitochondrial disorders; Obesity
What are the 5 main purposes for familial segregation analysis?
Identify genetic diseases running in the family Identify inheritance patterns Aid diagnosis Assist in management of condition Identify relatives at risk of disease
What is the segregation pattern of an autosomal dominant disease? Give an example
At least one parent affected M or F can be affected Vertical transmission e.g. Huntington's disease -cell death in basal ganglia -instable CAG triplet repeats
What is the segregation pattern of an autosomal recessive disease? Give an example
No affected parent Transmitted by M or F M or F affected Usually no family history e.g. Cystic fibrosis -Mutation in the CFTR gene on Ch7 -disrupts salt/water regulation = thick mucus
What is the segregation pattern of an X linked recessive disease? Give an example
No affected parents Transmitted by F Only M affected rarely f affected e.g. haemophilia -Blood clotting disorder
What are 3 variations of genetic heterogeneity?
Same gene, different mutations, different symptoms
e.g. Cystic fibrosis and CAVD
Same disease, different genes
e.g. Haemophilia A/B
Same disease, different genes, different inheritance
e.g. different forms of epidermolysis bullosa
Define incomplete penetrance
Symptoms not always present in an individual with a disease-causing condition
Define variable expressivity
Disease severity may vary between individuals with the same disease-causing mutation
Define epistasis
Interaction between disease gene mutations and other modifier genes that can affect phenotype
What is the mechanism of dominance and what are its implications for therapy?
Mutations = toxic protein Effects of mutated gene mask the normal copy Treatment -switch off mutant gene -neutralise toxic protein effects
What is the mechanism of recessivity and what are its implications for therapy?
Mutations = absence of functional protein
Treatment = restore activity of missing protein
-Replace gene/protein/affected tissue
What is the mechanism of co-dominance and what are its implications for therapy?
Mutations affect both mutated and normal genes apparent in people with both
e.g. sickle cell trait
Define genomic imprinting
One copy of gene is methylated and will not be transcribed
If deletion in an active gene, causes disease as no transcription occurs
What are the causes and symptoms of Prader-Willi syndrome?
Caused by loss of paternal chromosome 15 Symptoms: -Hyperphagia = obesity -Mental impairment -Behavioural problems -Short stature, small hands and feel -Delayed/incomplete puberty -Infertility
How can the symptoms of Prader-Willi be managed?
Diet restriction
Exercise to increase muscle mass
Growth hormones for short stature
Hormone replacement at puberty
What are the causes and symptoms of Angelman syndrome?
Caused by loss of maternal chromosome 15 Symptoms: -Developmental delay -Movement disorders -Behavioural uniqueness -Microcephaly -Seizures
How can the symptoms of Angelman be managed?
Anticonvulsant drugs
Physo
Communication therapy
How are mitochondrial disorders inherited?
Via females through oocytes
Both M and F affected
Variable phenotype due to heteroplasmy
What is MELAS, its symptoms and its diagnosis?
Mitochondrial Encephalopathy Lactic Acidosis and Stroke like episodes
Progressive, ultimately fatal
Muscle weakness, vomiting, seizures, headache, hemiparesis, dementia
Diagnosed by muscle biopsy
What is LHON, its symptoms and its diagnosis?
Leber’s Hereditary Optic Neuropathy
Bilateral, painless loss of central vision and optic atrophy
Degeneration of retinal ganglion cells
Most patients eventually blind
Diagnosed by blood test and opthamlmology findings
What are two inborn errors of metabolism currently included in the UK national neonatal screening progammes?
Phenylketonuria (PKU)
MCAD deficiency
What are the clinical features of PKU?
Blond hair, blue eyes - no melanin
Eczema
Must odour
What is the treatment available for PKU?
Early detection is key
Remove phenylalanine from diet and monitor levels
Protein supplements
Strict diet in pregnancy
What are the clinical features of MCAD deficiency?
Mutation in ACADM gene causes disorder in fatty acid oxidisation
Presents in infancy with episodic hypoketotic hypoglycaemia, vomiting, coma, etc
Fasting or metabolic stress causes impaired fatty acid oxidisation
What is the treatment available for MCADD?
Avoid fasting
Nutritional supplements @ times of increased stress
