3- Imprinting and mitochondrial Disorders

Question 1

What is imprinting?

Answer 1

A few genes are only expressed via the maternal or paternal allele. The other allele is permanently switched off. The genome has an imprint of parental origin

Question 2

What is Prader Willie syndrome.

Answer 2

It is caused by a lack of a functional paternal copy of the PWS critical region on chromosome 15 (q11 q13)
It happens due to a deletion of the critical region on the paternal chromosome (70%)
It can also happen due to inheritance of two maternal copies of chromosome 15 via maternal uniparental isodisomy (25%)
It can also happen due to translocations and point mutations (5%)

Symptoms include:
o Musclehypotonia, Hyperphagia, Obesity/diabetes, Mentalretardation, Shortstature, Smallhandsandfeet, Delayed/incompletepuberty, Infertile

Question 3

What is Angelman syndrome

Answer 3

Same cause, same area, same chromosome as Prader Willi syndrome, but this time, involves paternal uniparental isodisomy
Symptoms: Severedevelopmentaldelay, Poororabsentspeech, Gaitataxia, Happydemeanour”, Microcephaly, Seizures

Question 4

What is Uniparental isodisomy

Answer 4

disjunction in meiosis II causes one of the sex cells to come out with two copies of the chromosome in it, and one without any copies of the chromosome, and the other two are normal. Fertilisation of the gamete with two copies of the chromosomes with a normal monosomic gamete happens, but the chromosome from the parent contributing the single chromosome is lost, resulting in uniparental isodisomy

Question 5

What is MELAS

Answer 5

This is a progressive neurodegenerative disorder, presenting with muscle weakness, episodic seizures and headache, hemiparesis, vomiting and dementia
It is caused by single point mutations in several genes:
o MTTL1 – tRNA translates codon as phenylalanine instead of leucine during mitochondrial protein synthesis
o MTND1,MTND5–NADHdehydrogenase

Question 6

How is DNA inactivated

Answer 6

dna methylation

A methyl group is added to the pyramiding ring of cytosine

Question 7

What is heteroplasmy

Answer 7

In one cell there are mitochondria with different DNA

Question 8

What is LHON

Answer 8

This is optic neuropathy, loss of sight, most will become blind
It is bilateral and painless. There is loss of central vision and optic atrophy
Caused, over 90% of the time, by mutations in:
o MTND1, MTND4, MTND5, MTND6 and MTCYB – these code for NADH dehydrogenase subunits 1, 4, 5 and 6, and cytochrome b

Question 9

What does the UK newborn screening programme screen for

Answer 9

Phenylketonuria
o CongenitalHypothyroidism
o SicklycellDisorders
o Cysticfibrosis
o Medium chainacyl coAdehydrogenasedeficiency

Question 10

What is MCAD

Answer 10

This is the commonest disorder of fatty acid oxidation
It is caused by a deficiency of the enzyme medium chain acyl coA dehydrogenase
Patients must maintain an adequate calorie intake to prevent the switch to fatty acid oxidation

Question 11

What is PKU

Answer 11

This is caused by the deficiency of the enzyme phenylalanine hydroxylase, causing phenylalanine to accumulate. This is converted into phenylpyruvate, which is excreted in the urine
It also causes a tyrosine deficiency, leading to reduced melanin (so blonde+ blue eyes)
It manifests with severe mental retardation, and convulsions