More stories from the genetics clinic Flashcards by Georgia Leggett

Genomic Imprinting

Inherit only 1 working copy of a gene: maternal or paternal copy is epigenetically silenced.
Silencing occurs through the addition of methyl groups during egg or sperm formation.
In > 75 genes

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DNA Methylation

Addition of a methyl group to 5 position of pyrimidine ring of a cytosine
Occurs at CpG dinucleotides
Methylation in the promoter of a gene represses gene transcription

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When X is inactivated it is…

Hypermethylated

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Methylation patterns

vary between tissues and vary depending on age.
are affected by environment.
are potentially heritable

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Imprinting disorders

Caused by loss of function of 1 of 2 parental chromosomes.

Resulting syndrome depends on whether maternal or paternal chromosome loses function

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What happens when a certain part of Chromosome 15 in the paternal chromosome is deleted?

Paternal = Prader-Willi Syndrome (PWS)

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What happens when a certain part of Chromosome 15 in the maternal chromosome is deleted?

Maternal = Angelman Syndrome (AS)

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List 7 Symptoms of Prader-Willi syndrome

Hyperphagia: Obesity/Diabetes 
Mental impairment 
Muscle Hypotonia 
Short Stature 
Small Hands and Feet 
Delayed/Incomplete Puberty 
Infertility

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Management of Prader-Willi syndrome

Hyperphagia managed by diet restriction
Exercise to increase muscular mass
Growth hormone treatment for short stature
Hormone replacement at puberty

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Genetic Mechanism of Prader-Willi Syndrome

Caused by lack of a functional paternal copy of PWS critical region on 15q11- q13

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Causes of Prader-Willi syndrome and their prevalence

70% due to deletion of critical region on the paternal chromosome
25% due to inheritance of 2 maternal copies by uniparental isodisomy
5% due to other mechanisms e.g. translocations

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Uniparental Isodisomy

Zygote gets a pair of chromosomes from 1 parent not both.
Caused by failure to separate chromosomes in meiosis II and failure to remove correct chromosome following non-disjunction.

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How does Uniparental Isodisomy lead to Prader-Willi syndrome?

Results in 3 copies of Chr 15, (which would be fine if you deleted 1 copy).
But if paternal copy is deleted
There are only maternal copies
= Prader-Willi Syndrome

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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

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Is there another way to diagnose PWS and AS?

methylation-specific PCR

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Describe the PWS Critical region

Large

Has several genes

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As Prader-Willi and Angelman are both caused by loss of function of same region of Chr 15…

We expect them to be similar but they are not

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List 6 Symptoms of Angelman syndrome

Developmental Delay
Speech impairment 
Gait Ataxia 
'Happy Demeanour' 
Microcephaly 
Seizures

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Treatment of Angelman syndrome is symptomatic

Anti-Convulsant
Physiotherapy
Communication Therapy
Normal lifespan

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The Mitochondrial Genome

16.6kb, 37 genes
2-10 copies per mitochondrion
~2000 mitochondria per cell
Circular Genome - like bacterial plasmid

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Mitochondrial inheritance

maternally inherited from egg
Passed to all children regardless of gender
Variable phenotype due to heteroplasmy

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Heteroplasmy

In a single cell, there’s a mix of mitochondria, some containing mutant DNA and some containing normal DNA.

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Threshold of mitochondria at which heteroplasmy begins to cause disease

0-3 affected= NO DISEASE
5 affected= MILD DISEASE
9 affected= SEVERE DISEASE

List 5 mitochondrial diseases

MELAS 
LHON
MERRF 
DEAF 
NARP

What does MELAS stand for?

Mitochondrial myopathy Encephalopathy Lactic Acidosis Stroke

Describe MELAS

Progressive neurodegenerative disorder

List 5 Symptoms of MELAS

``` Muscle Weakness Episodic Seizures Headache Hemiparesis Vomiting Dementia ```

Why does MELAS affect muscles and brain?

both have high energy requirements and lots of mitochondria

What is treatment like in MELAS?

Symptomatic

How is MELAS diagnosed?

Muscle biopsy

MELAS is caused by which single mutations?

MTTL1: tRNA translates codon as Phenylalanine instead of Leucine during mitochondrial protein synthesis. MTND1, MTND5: NADH Dehydrogenase subunits 1 and 5

What does LHON stand for?

Leber's Hereditary Optic Neuropathy

Which gender is LHON more common in?

Males

Which age group does LHON affect?

20-30s

Symptoms of LHON

Bilaterial, painless, loss of central vision Optic Atrophy Eventually leads to BLINDNESS.

What is treatment like in LHON?

Symptomatic

How is LHON diagnosed?

Ophthalmological Findings | Blood Test for mtDNA Mutations

Where are the mutations that cause LHON?

``` NADH dehydrogenase subunits (MTND1, MTND4, MTND5, MTND6) Cytochrome B (MTCYB) ```

What could potentially be a prevention method for mitochondrial disorders?

3 parent babies

Inborn errors of metabolism

``` errors of metabolism, can be hereditary '1 gene - 1 protein' concept. >200 diseases known. Mostly autosomal recessive or X-linked Defective proteins are mainly enzymes. ```

UK newborn screening programme can test for inborn error of metabolism, it involves...

Physical exam Hearing test Heel prick test

What 5 diseases does the 'heel prick' test for?

``` Phenylketonuria Congenital Hypothyroidism Sickle Cell Disease Cystic Fibrosis MCAD Deficiency ```

What is Phenylketonuria (PKU) ?

Phenylalanine Hydroxylase Deficiency

What are the symptoms of Phenylketonuria (PKU)?

Blonde Hair/Blue Eyes Eczema If untreated: Severe Mental Retardation and Convulsions

Mechanism of action in PKU

Phenylalanine accumulates and is converted to phenylpyruvic acid - excreted in urine. Phenylalanine isn't converted into tyrosine (which is then converted into melanin) Tyrosine Deficiency = reduced melanin (reason for blonde hair and blue eyes)

Treatment of PKU

Remove phenylalanine from diet (and monitor levels) Protein supplements to supply other amino acids Strict diet in pregnancy

What does early detection and treatment of PKU result in?

No mental retardation No convulsions essentially no ill effects at all

Problems with the PKU diet

Difficult to stick to the diet | Aspartame (artificial sweetener in many diet drinks) contains phenylalanine

What is the commonest disorder of fatty acid oxidation?

MCAD deficiency

Where is the mutation in MCAD?

ACADM

If MCAD goes undiagnosed

25% mortality in 1st episode

How does MCAD present in infancy?

``` Episodic Hypoketotic Hypoglycaemia Vomiting Coma Metabolic Acidosis Encephalopathy ```

When is MCAD asymptomatic?

At baseline

What does fasting/ metabolic stress cause in those with MCAD?

Switch to fatty acid oxidation, but this is impaired Hypoglycaemia Hypoketosis

What is the treatment for MCAD?

Avoid fasting | Nutritional supplements at times of increased stress