Monogenic diseases

Question 1

Explain the utility of familial segregation analysis, summarise a family history by generating a pedigree diagram

and be able to generate a genetic risk assessment based on pedigree analysis

Answer 1

Why are pedigree diagrams important?

1. Identify genetic disease running in family
2. Identify inheritance patterns
3. Aid diagnosis
4. Assist in management of condition
5. Identify relatives at risk of disease

They want us to be able to read a pedigree and conclude in some risk assesments

Question 2

List examples of recessive and dominant autosomal and X-linked disorders and explain their segregation patterns; explain mechanisms of dominance, co-dominance and recessivity and their implications for therapy

Answer 2

Autosomal Dominant;

1. At least one parent is affected
2. Can be transmitted by both the Mother and the Father
3. Mother or Father is affected
4. Vertical Transmission

ex. Huntington’s disease

1. The HTT gene on chromosome 4 encodes for huntigtin protein ( HD patients inherit a mutated form which is toxic and causes the formation of “clumbs” causing CELL DEATH in the BASAL GANGLIA
2. Motor, cognitive + psychiatric dysfunction ‘hyperkinesia’
3. Is usually diagnosed at around 35-44 yrs old and it’s survival is 15-18 yrs
4. Treatment eases symptoms, no cure
5. Caused by INSTABLE CAG triplet repeats which may expand with generations which decreases the survival as generations pass ( age of onset decreases and severuty increases)

Autosomal Recessive;

1. There is no affected parent
2. Usually no family history

ex. Cystic fibrosis ( testing part of UK screening programme)

1. Chronic life-threatening condition
2. Symptoms: mucus in lungs affects lung function, blockages in pancreas
3. Treatment: daily enzymes, physio
4. 1 in 22 in UK carrier
5. Mutation in CFTR gene on Ch 7 (encodes Cl- channel). Disruption salt/water regulation on epithelial cells resulting in thick mucus and symptoms

Same gene, different symptoms;

Congenital Absence of the Vas Deferens ( CAVD) causes infertility. Most cases are caused by mutations in the CFTR gene.

X-linked recessive;

1. No affected parents
2. Only males are affected
3. Transmitted by Females

ex Heamophilia

1. Blood clotting disorder => easy bruising, heavy bleeding
2. 2 types: Haemophili A + B (rarer)
3. Treatment: clotting factor injections
4. Haemophilia A: F8 gene on chr. X encodes protein coagulation factor 8
5. Haemphilia B: F9 gene on chr. X encodes protein cogulation factor 9
6. This is an example of the same disease but different genes

Definitions;

1. Incomplete penetrance: symptoms are not always present in an individual with a disease-causing mutation
2. Variable expressivity :disease severity may vary between individuals with the same disease-causing mutation
3. Phenocopy: having the same disease but with a different underlying cause
4. Epistasis: interaction between disease gene mutations and other modifier genes can affect phenotype

To conclude;

1. Same gene, different mutations, defferent symptoms; cystic fibrosis and CAVD are both caused by mutations in the CTFR gene
2. Same disease, different genes; Haemophilia A/B
3. Same disease, different genes, difference inheritance patters: different forms of epidermolysis bullosa can be AD or AR

Molecular Mechanisms

1. Dominant;
   
   • presence of toxin protein (mutated gene masks normal copy)
   • neutrilize toxin or switch off mutated gene
2. Recessive;
   
   1. absence of a functional protein
   2. restore activity by replacing the gene or the protein
3. Co-dominant; afects both mutated and normal genes ( depends on how much a patients is affected)

Question 3

Explain what is meant by epigenetics; list two specific examples of genomic imprinting disorders, outlining possible mechanisms, clinical features and transmission patterns

Answer 3

Epigenetics;

• no change in the genetic sequence but there are some heritable changes ( chemical modification; methylation)

Genomic imprinitng;

• when form the two copies inherited by parents 1 is turned on
• this might depend on where the gene came from (sometimes gene from the father are active)

Methylation;

• addition of a methyl group (-CH₃) on the 5’ position of a Cytostine
• responsible from imprinting and X-innactivation
• can sometimes be retained from our parents and passed on to the next generation

Uniparental disomy (UPD);

• when a person receives two copies of a chromosome OR part of a chromosome from one parent and no copies from the other.

Chromosome 15 imprinting disorders;

PRADER- WILLI SYNDROME (loss of paternal)

Symptoms:

1. Hyperphagia => obesity
2. Mental impairment
3. Behavioral problems
4. Muscle hypotonia
5. Short stature, small hands + feet
6. Delayed/ incomplete puberty, infertility

Management:

1. Hyperphagia= diet restriction
2. Exercise to increase muscle mass
3. GH for short stature
4. Hormone replacement at puberty

ANGELMAN SYNDROME (loss of maternal)

Symptoms:

1. Developmental delay + speech impairment
2. Movement disorder (ataxia, tremulous limb movement)
3. Behavioral uniqueness: happy demeanors, excitable, short attention span
4. Microcephaly
5. Seizures (<3 yrs onset)

Management:

1. Symptomatic- anticonvulsant, physio, communication therapy
2. Normal life span

Question 4

List two examples of mitochondrial disorders, explaining transmission patterns and the implications of heteroplasmy for counseling

Answer 4

Mitochondrial genome;

1. 37 genes encoding resp complexes, tRNA, rRNA
2. 2-10 copies per mitochondriun
3. it is always inherited from the mother via oocytes
4. phenotype is variable due to heteropasmy

Diseases;

MELAS (Mitochondrial Encephalopathy Lactic Acidosis and Stroke-like episodes)

1. Progressive neurological disorder that is ultimately fatal
2. Muscle weakness
3. vomiting
4. episodic seizures
5. headache
6. hemiparesis
7. dementia

Diagnosis: muscle biopsy

Treatment: symptomatic

Genetics: single mutations in several genes

LHON (Lebers Hereditary Optic Neuropathy)

1. More common in males (unclear why)
2. Degeneration of retinal ganglion cells
3. Bilateral, painless, loss of central vision + optic atrophy
4. 20 yrs = average age of onset
5. Most patients eventually become blind

Diagnosis; ophthalmology findings + blood test for mtDNA mutations

Treatment; symptomatic

Question 5

List two examples of inborn errors of metabolism currently included in UK national neonatal screening programmes, including clinical features and therapeutic management of each condition

Answer 5

UK Newborn Screening programme

1. Physical exam
2. Hearing test
3. Blood spot test for genetic diseases – many FOCUS on: PKU + MCADD

Phenylketonuria PKU

1. Phenylalanine hydroxylase (PAH) deficiemcy
2. >600 genetic mutations described

SYMPTOMS:

1. • Blond hair/blue eyes (no melanin)
2. • Eczema, must odour (excess phenylacetate)

TREATMENT:

1. Early detection
2. Remove phenylalanine from diet + monitor levels
3. Protein supplements to supply other amino acids
4. Strict diet in pregnancy (risk of growth retardation + heart defects)

UNTREATED: seizures + severe mental retardation

MCADD deficiency

1. Most common disorder of fatty-acid oxidation
2. MCAD = Medium-Chain Acyl-CoA Dehydrogenase
3. Mutation in ACADM gene (85% A985G)
4. Presents in infancy with:
   
   1. Episodic hypoketotic hypoglycaemia
   2. vomiting, coma, metabolic acidosis, encephalopathy
5. Undiagnosed => 25% mortality of first episode

Mechanism

1. Asymptomatic at baseline
2. Fasting or metabolic stress –>switch to fatty acid oxidation, but impaired
3. Hypoglycaemia
4. Hypoketosis

Treatment:

1. Avoiding fasting
2. Nutritional supplements at times of increased stress

Question 6

List defects in the leptin-melanocortin pathway leading to three forms of monogenic obesity

Answer 6

Leptin;

1. Hormone made by adipocytes in white adipose tissue
2. Circulates in plasma in proportion to amount of adipose tissue
3. Acts on hypothalamus (arcuate nucleus) => inhibits appetite
4. LOW when LOW body fat
5. HIGH when HIGH body fat

Types of Obesity;

1. Monogenic; dominant or recesive single gene disorders
2. Syndromic; ex Prader Willi syndrome
3. Common obesity; obesity in the general population

Monogenic Leptin deficiency; Hunger, obesity, no puberty, poor growth, low thyroid, immune problems

Genes causing single gene obesity;

• Dominant
  
  1. MC4R – most common single-gene form of obesity (2-6%)
• Recessive
  
  1. PCSK1 – obesity
  2. POMC – red hair, obesity, adrenal insufficiency
  3. MRAP2 - obesity

All of the above affect appetite regulation

Managment; lifestyle measures, medication, Bariatric surgery