Lecture 3- More stories from the genetics clinic Flashcards
What is epigenetic modification? (w.r.t. DNA methylation)
- No change in genetic sequence
- DNA methylation- addition of methyl group to 5’ of pyramiding ring of cytosine
- occurs in humans at CpG dinucleotides
What does methylation at the gene promoter cause?
Represses gene transcription
What is genomic imprinting?
- Non-mendelian inheritance
- the genome carries an imprint or ‘stamp’ of its parental origin
What causes genomic imprinting?
DNA methylation and epigenetic modification
List two example of genetic imprinting disorders
Prader-WIlli (Paternal) Angelman syndrome (Maternal)
What are the symptoms of Prader Willi syndrome?
Hyperphagia --> obesity Mental impairment Behaviuoral problems Muscle Hypotonia Shrort, stature, small hands and feet Delayed/ incomplete puberty --> infertility
How is Prader-WIlli syndrome managed?
- Diet restriction (hyperplasia)
- Exercise to increase muscle mass (hypotonia)
- GH treatment (short stature)
- HRT (for delayed puberty)
What are the symptoms of Angelman syndrome?
- development delay and speech impairment
- movement disorder
- Behavioural uniqueness (happy, excitable etc)
- microcephaly
- seizures
How is Angelman Syndrome diagnosed?
- Clinica features and molecular diagnosis
What is the treatments for Angelman?
Symptomatic- anti-convulsant, physiotherapy, communication therapy
- Normal life span
Describe the structure of the mitochondrial genome
- 37 genes
- Code for: tRNA, rRNA, respiratory complexes
- circular DNA
- 2-10 plasmids per mt
How are mitochondria inherited?
Through females via oocyte
Why can the phenotype of mitochondrial inheritance vary?
Heteroplasmy- cell contains diseased and non-diseased mitochondria
Give two examples of mitochondrial disorders
MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke like episodes)
LHON (Leber’s Hereditary Optic Neuropathy)
What are the symptoms of MELAS?
Muscle weakness Vomiting Episodic seizures Headache Hemiparesis Dementia
How is MELAS diagnosed and treated?
Muscle biopsy
Symptomatic treatment
What is the genetic mechanism behind MELAS?
- single mutation in several genes
1) MTTL1: tRNA translates codon as Phe instead of Leu during mt protein synthesis
2) MTND1, MTND5: NADH dehydrogenase subunits 1 and 5
What are the symptoms of Lebers?
- degeneration of retinal ganglion cells
- Bilateral, painless, loss of central vision
- Optic atrophy
- average age of onset 20
- more common in males
How is Leber’s diagnosed?
- ophthalmological findings
- Blood test for mtDNA mutations
Which genes might be mutated in LHON?
- MTND1, MTND4, MTND5, MTND6: NADH dehydrogenase subunits
- Cytochrome B MTCYB
Which genetic diseases are newborns screened for and how?
Heel prick test
- Sickle cell diseas
- Cystic fibrosis
- Congenital hypothyroidism
- Phenylketonuria
- MCADD
What are the symptoms of phenylketonuria?
- lack of melanin
- eczema, musty odour (excess of phenyl acetate)
Can lead to: - seizures
-severe mental retardation
What causes the lack of melanin in PKU?
Tyrosine deficiency
What causes severe mental retardation in PKU?
Phenylalanine hydroxylase deficiency –> Phenylalanine accumulation–> converted to phenylpyruvic acid –> excreted in urine
What is the treatment for PKU?
- early detection
- remove Phenylalanine from diet
- protein supplements to supply other amino acids
- strict diet in pregnancy
What are the symptoms of MCADD?
- Episodic hypoketotic hypoglycaemia
- Vomiting, coma, metabolic acidosis, encephalopathy
- 25% mortality if undiagnosed
What is the treatment for MCADD?
- avoid fasting
- nutritional supplements
