What is imprinting?
Some genes are only expressed via the maternal or paternal allele. The other allele is permanently switched off. This imprinting is reversible and occurs via the process of DNA methylation. The 5th position of the pyrimidine ring of cytosine at a CpG dinucleotide.
Give examples of imprinting disorders
On chromosome 15 there is a region containing both maternally and paternally expressed genes. If the paternal chromosome is damaged then Prader Willi syndrome occurs and if the maternal chromosome is damaged then Angelman’s syndrome occurs.
Describe the features of Angleman’s syndrome - symptoms and causes
Symptoms:
- severe developmental delay
- poor/absent speech
- happy demeanor
- microcephaly
- seizures
- treated symptomatically - anticonvulsants and physiotherapy
- normal life span
Cause:
- paternal uniparental isodisomy
Describe the features of Prader Willi’s syndrome - symptoms and causes
Symptoms:
- Hyperphagia
- Obesity/Diabetes
- Mental Retardation
- Muscle Hypotonia
- Short Stature
- Small Hands and Feet
- Delayed/Incomplete Puberty
- Infertility
Causes:
- lack of functional paternal copy (deletion)
- due to inheritance of two maternal Chr 15 via maternal uniparental isodisomy
- translocations or point mutations
What is uniparental isodisomy?
- Non dysjunction occurs during meiosis 2
- One gamete has 2 copies of the chromosome and one has no copies
- fertilisation of the one with 2 copies happens but the one from the parent contributing one copy is lost
How is Prader Willi/Angelman syndrome diagnosed?
FISH - fluorescently labelling regions on chromosomes
PML (Promyelocytic Leukaemia) gene is present on Chr 15 outside PWS/AS region.
SNRPN (small nuclear ribonucleoprotein polypeptide N) is present inside the PWS/AS reg
Methylation specific PCR
What is heteroplasmy?
Not all of the mitochondria are damaged so the severity of the condition may vary.
- When there are 0-3 affected mitochondria, no disease
- When there are 5 affected mitochondria, there is mild disease
- When there are 9 affected mitochondria, there is severe disease
What are the implications of heteroplasmy on counselling?
- uncertainty
- can’t eliminate stress
- hope for family
- more difficult for family to make a decision
How much DNA is contained in the mitochondria?
37 genes
2-10 copies per mitochondrion
2-2500 mitochondria per cell
How do only females transmit mitochondria?
Only transmitted through females because the ovum has mitochondria. When it meets the sperm, the sperm loses
its mitochondria and only the DNA gets through.
What are some examples of mitochondrial diseases?
MELAS LHON MERRF DEAF NARP
What is LHON?
Symptoms, causes, management and diagnosis
Leber’s Hereditary Optic Neuropathy
- Affects people on average in their mid 20s to mid 30s.
Symptoms:
- Bilaterial, painless, loss of central vision
- Optic Atrophy
- Blindness
(mitochondria in the optic nerve is damaged so it dies)
Treatment is symptomatic
Diagnosis:
- Ophthalmological Findings
- Blood Test for mtDNA Mutations
Causes:
- Mutations in MTND 1, 4, 5 and 6 - NADH dehydrogenase subunits 1, 4, 5 and 6.
- Mutation in MTCYB - Cytochrome B
What is MELAS?
Symptoms, causes, management and diagnosis
Mitochondrial myopathy, Encephalopathy, Lactic Acidosis and Stroke
- Progressive neurogenerative disorder
- Affects the muscles and the brain because they both have high energy requirements and hence a lot of mitochondria.
Symptoms:
- Muscle Weakness
- Episodic Seizures and Headache
- Hemiparesis (weakness on one side of the body)
- Vomiting
- Dementia
Treatment is symptomatic
Diagnosis is by muscle biopsy
Causes:
- MTTL1 - tRNA translates codon as phenylalanine instead of leucine during mitochondrial protein synthesis
- MTND1, MTND5 - NADH Dehydrogenase subunits 1 and 5
What are newborns screened for in the UK in the heel prick test?
- Phenylketonuria
- Congenital Hypothyroidism
- Sickle Cell Disease
- Cystic Fibrosis
- Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCAD Deficiency)
- Homocystinuria
- Maple Syrup Urine Disease
- Glutaric Aciduria type 1
- Isovaleric Acidaemia
What is phenylketonuria - symptoms and causes?
Phenylalanine Hydroxylase Deficiency (causes the severe mental retardation)
Phenylalanine accumulates and is converted to phenylpyruvic acid - excreted in urine. The reason for the blonde hair and blue eyes is the tyrosine deficiency. Phenylalanine isn’t converted into tyrosine (which is then converted into melanin).
- Severe Mental Retardation and Convulsions
- Blonde Hair/Blue Eyes
- Eczema
- Tyrosine Deficiency - reduced melanin
What is MCAD?
Symptoms and causes
Commonest disorder of fatty acid oxidation. Commonly presents when the baby is older than 3 months.
- Episodic Hypoketotic Hypoglycaemia
- Coma
- Metabolic Acidosis
- Encephalopathy (brain damage)
- Sudden Death
MCAD = Medium Chain Acyl-CoA Dehydrogenase
If you get rid of MCAD, you fail to process fats into something useful. When your blood glucose goes down you would normally switch to b-oxidation but if that can’t happen then you have no source of energy for the cell.
Treatment for phenylkutonuria
You screen for elevated levels of phenylalanine in the blood. Then you remove phenylalanine from the diet if you suspect that the patient has PKU.
Early Detection = No Mental Retardation, no convulsions
Problems with the diet:
- Difficult to stick to
- Aspartame (artificial sweetener in many diet drinks) contains phenylalanine
- Pregnant women need to go back on the diet in case their child has PKU
What is the treatment for MCAD?
- Maintenance of adequate calorie intake to prevent switch to fatty acid oxidation.
- Avoid fasting
- Honey or glucose drip
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
