More Stories from the Genetics Clinic Flashcards
what are other types of genetics disease?
- imprinting disorder - mitochondrial disorders - inborn errors of metabolism
examples of imprinting disorders
o Prader-Willi o Angelman
examples of mitochondrial disorders
o MELAS o LHON
examples of inborn errors of metabolism
o Phenylketonuria o MCAD Deficiency
features of inborn errors of metabolism?
- autosomal recessive - defective proteins are normally enzymes
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 it is a reversible epigenetic effect
What is the mechanism of imprinting?
DNA Methylation
Which base gets methylated?
5’ position on the pyrimidine ring of the cytosine
What is the general effect of methylation on the gene promoter?
Repressed gene transcription - this is the underlying principle of imprinting - when X is inactivated it is hypermethylated
The loss of function of a gene on which chromosome causes Prader-Willi and Angelman Syndrome?
Chromosome 15 prader willi - male angelman syndrome - female
State some symptoms of Prader-Willi Syndrome
Hyperphagia - excessive hunger Obesity Mental Retardedness Short Stature Hypotonia Infertility
how to manage prader willi syndrome?
- diet restriction - exercise to increase the muscle mass - growth hormone treatment for shortness - hormone replacement at puberty
State some symptoms of Angelman Syndrome.
- Microcephaly (small brain and small head) - Poor or absent speech - Gait ataxia (uncoordinated movements) - Severe developmental delay - seems happy - NORMAL LIFESPAN
treatment of angelman syndrome:
- anticonvulsant - physiotherapy - communication therapy
explain the deletion of the PWS critical:
this overall region is large and has several genes - the deletions might be type 1 (BP1 - BP3) type 2 (BP2-BP3)
What are the three possible causes of Prader-Willi and Angelman Syndrome?
- Deletion of the PWS/AS critical region on chromosome 15 - Uniparental isodisomy - Other mechanisms e.g. translocations
Describe how uniparental isodisomy can lead to Prader-Willi and Angelman Syndrome.
a zygote that has a pair of chromosomes from one parent not both 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. - overall this is caused by failure to separate the chromosomes in meosis ii and failure to delete the correct chromosome following the non disjunction
How is PWS and AS diagnosed? Which genes near/in the PWS/AS critical region are used?
- FISH – 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
What phenomenon determines the severity of mitochondrial disease?
Heteroplasmy - the situation in which within a single cell there is a mixture of mitochondria, some containing mutant DNA and some containing normal DNA 0-3 affected mitochondria no disease 5 affected means mild disease 9 affected means severe disease
what are newborns screened for and how?
• Phenylketonuria • Congenital Hypothyroidism • Sickle Cell Disease • Cystic Fibrosis • Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCAD Deficiency) heel prick test
describe the mitochondrial genome:
- 16.6 kb - 37 genes - 2-10 copies per mitochondrion - 2-2500 mitochondria per cell - circular genome - like bacterial plasmid
State two examples of mitochondrial disease
MELAS and LHON
is mitochondria transmitted through males or females?
- only transmitted through the females - the ovum has mitochondria - when the sperm meets the ovum it loses its mitochondria and only the DNA gets through - mitochondrial disease can affect males and females
State some symptoms of MELAS.
Mitochondrial encephalomyopathy (muscle weakness) Lactic Acidosis (vomiting, diarrhoea) Stroke Episodic seizures, headache, hemiparesis MELAS affects the muscles and the brain because they both have high energy requirements
What mutations cause MELAS?
single mutations MTTL1 – tRNA translated codon as Phenylalanine instead of leucine MTND1 and MTND5 – NADH Dehydrogenase subunits 1 and 5
State some symptoms of LHON lebers hereditary optic neuropathy how is LHON diagnosed?
- more common in males - affects people in 20s and 30s Painless bilateral loss of central vision leading to blindness o Ophthalmological Findings o Blood Test for mtDNA Mutations
Mutations in what genes cause LHON?
MTND1, 4,5 and 6 – NADH Dehydrogenase subunits 1, 4, 5 and 6 MTCYB – cytochrome B
Give two examples of inborn errors of metabolism.
Phenylketonuria and MCAD deficiency
State some symptoms of Phenylketonuria
Mental retardation (due to the phenylalanine hydroxylase deficiency) Blonde hair/blue eyes (tyrosine deficiency) Eczema
How is phenylketonuria detected?
Elevated levels of phenylalanine in the blood
What is the treatment for PKU? what are problems with the diet?
Remove phenylalanine from the diet - it is difficult to stick to the diet - there are artificial sweeteners in lots of drinks
what is an MCAD deficiency?
- it is the commonest disorder of fatty acid oxidation - Episodic Hypoketotic Hypoglycaemia - presents when the baby is older than 3 months - sudden death sometimes happens • MCAD = Medium Chain Acyl-CoA Dehydrogenase
A mutation in which gene causes MCAD Deficiency? and what does it result in?
ACADM - with no MCAD you fail to process fats into something useful - when your blood glucose goes down normally we switch to beta oxidation but this cannot happen if there is no source of energy for the cell
What is the treatment for MCAD Deficiency?
Maintain adequate calorie intake to prevent the body from switching to beta-oxidation. - must avoid fasting
what are the symptoms, diagnosis of MELAS?
- hyperintense signals in the MRI do not correspond directly to the stroke - the treatment is based on symptoms - diagnosis is by muscle biopsy
