More Stories from the Genetics Clinic

Question 1

what are other types of genetics disease?

Answer 1

• imprinting disorder - mitochondrial disorders - inborn errors of metabolism

Question 2

examples of imprinting disorders

Answer 2

o Prader-Willi o Angelman

Question 3

examples of mitochondrial disorders

Answer 3

o MELAS o LHON

Question 4

examples of inborn errors of metabolism

Answer 4

o Phenylketonuria o MCAD Deficiency

Question 5

features of inborn errors of metabolism?

Answer 5

• autosomal recessive - defective proteins are normally enzymes

Question 6

What happens if the full genome of an embryo derives from one parent and what is the significance of this finding?

Answer 6

Paternal – hydatidiform mole Maternal – ovarian teratoma Shows that the origin of the parental DNA is important it is a reversible epigenetic effect

Question 7

What is the mechanism of imprinting?

Answer 7

DNA Methylation

Question 8

Which base gets methylated?

Answer 8

5’ position on the pyrimidine ring of the cytosine

Question 9

What is the general effect of methylation on the gene promoter?

Answer 9

Repressed gene transcription - this is the underlying principle of imprinting - when X is inactivated it is hypermethylated

Question 10

The loss of function of a gene on which chromosome causes Prader-Willi and Angelman Syndrome?

Answer 10

Chromosome 15 prader willi - male angelman syndrome - female

Question 11

State some symptoms of Prader-Willi Syndrome

Answer 11

Hyperphagia - excessive hunger Obesity Mental Retardedness Short Stature Hypotonia Infertility

Question 12

how to manage prader willi syndrome?

Answer 12

• diet restriction - exercise to increase the muscle mass - growth hormone treatment for shortness - hormone replacement at puberty

Question 13

State some symptoms of Angelman Syndrome.

Answer 13

• Microcephaly (small brain and small head) - Poor or absent speech - Gait ataxia (uncoordinated movements) - Severe developmental delay - seems happy - NORMAL LIFESPAN

Question 14

treatment of angelman syndrome:

Answer 14

• anticonvulsant - physiotherapy - communication therapy

Question 15

explain the deletion of the PWS critical:

Answer 15

this overall region is large and has several genes - the deletions might be type 1 (BP1 - BP3) type 2 (BP2-BP3)

Question 16

What are the three possible causes of Prader-Willi and Angelman Syndrome?

Answer 16

• Deletion of the PWS/AS critical region on chromosome 15 - Uniparental isodisomy - Other mechanisms e.g. translocations

Question 17

Describe how uniparental isodisomy can lead to Prader-Willi and Angelman Syndrome.

Answer 17

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

Question 18

How is PWS and AS diagnosed? Which genes near/in the PWS/AS critical region are used?

Answer 18

• 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

Question 19

What phenomenon determines the severity of mitochondrial disease?

Answer 19

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

Question 20

what are newborns screened for and how?

Answer 20

• Phenylketonuria • Congenital Hypothyroidism • Sickle Cell Disease • Cystic Fibrosis • Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCAD Deficiency) heel prick test

Question 21

describe the mitochondrial genome:

Answer 21

• 16.6 kb - 37 genes - 2-10 copies per mitochondrion - 2-2500 mitochondria per cell - circular genome - like bacterial plasmid

Question 22

State two examples of mitochondrial disease

Answer 22

MELAS and LHON

Question 23

is mitochondria transmitted through males or females?

Answer 23

• 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

Question 24

State some symptoms of MELAS.

Answer 24

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

Question 25

What mutations cause MELAS?

Answer 25

single mutations MTTL1 – tRNA translated codon as Phenylalanine instead of leucine MTND1 and MTND5 – NADH Dehydrogenase subunits 1 and 5

Question 26

State some symptoms of LHON lebers hereditary optic neuropathy how is LHON diagnosed?

Answer 26

- 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

Question 27

Mutations in what genes cause LHON?

Answer 27

MTND1, 4,5 and 6 – NADH Dehydrogenase subunits 1, 4, 5 and 6 MTCYB – cytochrome B

Question 28

Give two examples of inborn errors of metabolism.

Answer 28

Phenylketonuria and MCAD deficiency

Question 29

State some symptoms of Phenylketonuria

Answer 29

Mental retardation (due to the phenylalanine hydroxylase deficiency) Blonde hair/blue eyes (tyrosine deficiency) Eczema

Question 30

How is phenylketonuria detected?

Answer 30

Elevated levels of phenylalanine in the blood

Question 31

What is the treatment for PKU? what are problems with the diet?

Answer 31

Remove phenylalanine from the diet - it is difficult to stick to the diet - there are artificial sweeteners in lots of drinks

Question 32

what is an MCAD deficiency?

Answer 32

- 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

Question 33

A mutation in which gene causes MCAD Deficiency? and what does it result in?

Answer 33

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

Question 34

What is the treatment for MCAD Deficiency?

Answer 34

Maintain adequate calorie intake to prevent the body from switching to beta-oxidation. - must avoid fasting

Question 35

what are the symptoms, diagnosis of MELAS?

Answer 35

- hyperintense signals in the MRI do not correspond directly to the stroke - the treatment is based on symptoms - diagnosis is by muscle biopsy