More stories from the genetic clinic Flashcards
What happens if the full genome of an embryo derives from one parent and what is the significance of this finding?
Paternal – hydatidiform mole
Maternal – ovarian teratoma Shows that the origin of the parental DNA is important
What is the mechanism of imprinting and X-chromosome inactivation
DNA Methylation
Which base gets methylated?
5’ position on the pyrimidine ring of the cytosine. This only occurs in humans at CpG dinucleotides ( Where cytosine nucleotide is followed by a guanine nucleotide in the 5’-3’ direction)
What is involved in DNA methylation to occur?
SAM is S-Adenosyl Methionine (source of the methyl group) and DNMT is DNA Methyltransferase (the catalytic enzyme)
What is the general effect of methylation on the gene promoter?
Repressed gene transcription
The loss of function of a gene on which chromosome causes the 2 imprinting disorders and which parental chromosome is responsible for each?
Chromosome 15
Paternal- Prader Willi
Maternal- Amgelman
What are the symptoms of prader willi syndrome and management of it
Hyperphagia-obesity Mental impairment (avg. IQ 60-70) Behavioural problems Muscle hypotonia Short stature, small hands and feet Delayed/incomplete puberty, infertility
Management:
- Hyperphagia- diet restriction
- exercise to increase muscular mass
- growth hormone treatment for short stature
- hormone replacement at puberty
State some symptoms of Angelman Syndrome and the managment.
- Severe developmental delay
- poor or absent speech
- gait ataxia
- happy demeanour
- microcephaly ( incomplete development of the brain)
- seizures
Management:
- Symptomatic- anticonvulsant (used to prevent or reduce the severity of epileptic fits or other convulsions.), physio, communication therapy
- Normal life span
What are the three possible causes of Prader-Willi and Angelman Syndrome?
Deletion of the PWS/AS critical region on chromosome 15
Uniparental disomy - Failure to separate the chromosomes in meiosis II and the failure to remove the correct chromosome following the non-disjunction.
mutation in an imprinting region.
What are some of the treatments of angelman syndrome?
-Anti-convulsant ( to reduce severity of epileptic fits)
-physiotherapy
-communication therapy
NORMAL LIFE SPAN
Describe how uniparental disomy can lead to Prader-Willi and Angelman Syndrome.
Non-disjunction in meiosis 2 makes a gamete that has two copies of chromosome 15 resulting in a zygote with three copies of chromosome 15. Failure to remove the duplicated chromosome results in the zygote having two copies of chromosome 15 from the same parent.
How is PWS and AS diagnosed? Which genes near/in the PWS/AS critical region are used?
FISH – fluorescence in situ
hybridisation. Fluorescently labelling regions on chromosomes.
PML (promyelocytic leukaemia) gene is just outside the PWS/AS critical region snRNP (small nuclear ribonucleoprotein) gene is inside the PWS/AS critical region.
As prader willi syndrome and angelman are caused by the loss of the function of the same region of chr 15, you would expect them to be similar but they are not.
How else can PWS and AS be diagnosed?
Using methylation-specific PCR.
What is heteroplasmy
The situation in which, within a single cell, there is a mixture of mitochondria ( energy producing cytoplasmic organelles), some containing mutant DNA and some containing normal DNA.
State two examples of mitochondrial disease
Mitochondrial Encephalomyopthy with Lactic Acidosis and Stroke-like episodes (MELAS)
&
Leber’s Hereditary Optic Neuropathy (LHON)
State some symptoms of MELAS and what part of the body it affects
Muscle weakness, Vomiting, Episodic seizures and headache, hemiparesis( weakness on one side of the body), Dementia.
MELAS affects the muscles and the brain because they both have high energy requirements and hence a lot of mitochondria.
How is MELAS diagnosed?
Diagnosis by muscle biopsy
What mutations cause MELAS?
MTTL1 – tRNA translates codon as Phenylalanine instead of leucine during mitochondrial protein synthesis
MTND1 and MTND5 – NADH Dehydrogenase subunits 1 and 5
State some symptoms of LHON
Bilateral, Painless, loss of central vision
optic atrophy
eventually leads to blindness.
Mutations in what genes cause LHON?
MTND1, 4,5 and 6 – NADH Dehydrogenase subunits 1, 4, 5 and 6 MTCYB – cytochrome B
How is LHON diagnosed?
- opthalmological findings
- blood test for mtDNA mutations
State some symptoms of Phenylketonuria
-Mental retardation caused by phenylalanine hydroxylase deficiency
-Blonde hair/blue eyes
Tyrosine deficiency- reduced melanin
-Phenylalanine accumulates and is converted to phenylpyruvic aicd- excreted in urine
-Eczema and musty odour
How is phenylketonuria detected?
Elevated levels of phenylalanine in the blood
What is the treatment for PKU?
Remove phenylalanine from the diet and give protein supplements to supply amino acids.
