List of Case Studies

Question 1

Xeroderma Pigmentosum (XP)

Answer 1

• Exposure to UV forms pyrimidine dimers (A and T).
• Nucleotide Excision Repair (NER) mechanism removes these in normal people.
• XP is an autosomal recessive disease caused by NER not working properly, resulting in base pair substitutions.
• Symptoms of XP are dry/scaly skin (xeoderma), extensive freckling, abnormal skin pigmentation (pigmentosum) and skin tumours.
  NER system
  NER System Mechanism
• The system is encoded by at least 28 different genes and a mutation in any of these genes can give rise to XP.
  1. The genes encode helicase unwind the double strand of DNA.
  2. An endonuclease cuts the DNA at the site of the dimer.
  3. An exonuclease removes the dimer.
  4. A polymerase fills the gap with DNA bases.
  5. A ligase that joins the corrected portion of DNA to the original strand.

Question 2

Rubinstein-Taybi Syndrome

Answer 2

**Causes **
- Mutations in the EP300 gene
- Mutations in the CREBBP gene, individuals with this disease only produce half of the normal amount of CREB binding protein.
* * - Deletion of genetic material on the short arm of chromosome 16 - multiple genes are missing as a result of this (eg. CREBBP gene).
* * * Characteristics
* * - Autosomal dominant
* * - Short stature
* * - Moderate to severe intellectual disabilty
* * - Distinctive facial features
* * - Broad thumbs and first toes
* * - Eye abnormalities, heart and kidney defects, dental problems, obesity, increased risk of non-cancerous skin and brain tumours

Question 3

CHOPS Syndrome

Answer 3

Causes
* Mutation in the AFF4 gene which encodes for making the protein complex called super elongation complex (SEC), involved in transcription. Mutations in the AFF4 gene produces excess AFF4 protein which interferes with normal pauses in transcription.
Characteristics
* Autosomal dominant
* Cognitive impairment
* Coarse facial features
* Heart defects
* Obesity
* Pulmonary issues
* Short stature
* Skeletal abnormalities

Question 4

MECP2 Duplicaton Syndrome

Answer 4

MECP2
* Involved in the reguation of gene expression
* MECP2 gene encodes for MECP2 protein
MECP2 Duplication Syndrome
* MECP2 is duplicated
Characteristics
* X - Linked disorder
* Intellectual disability
* Delayed development
* Seizures
* Males more affected than females
* Occurs as a result of a copy number variant (CNV) which are repeats longer than 100bp - entire genes can be deleted or duplicated multiple times which can occur by many different mechanisms

Question 5

Rett Syndrome

Answer 5

Causes
* Mutation or deletion in the MECP2 gene
* X - Linked disorder
Characteristics
* Normal at birth but can develop problems with communication and coordination
* Small head, breathing abnormalities, seizures, sclerosis and sleep disturbances
* Affects almost exclusively females

Question 6

Fragile X - Syndrome

Answer 6

Causes
* Caused by a mutation in the FMR1 gene which codes for a protein called FMRP.
* FMRP helps regulate the production of other proteins and plays a role in the development of synapses.
* Most cases are caused by a mutation in which a DNA segment,known as the CGG triplet repeat is expanded within the FMR1 gene is repeated more than 200 times (the repeat occurs 5 - 10 times in normal cases). The expanded segment silemces the FMR1gene which stops the gene from producing FMRP.
Characteristics
* X - linked disorder
* Affects 1 in 4,000 males and 1 in 8,000 females
* Mild to moderate intellectual disability
* Long and narrow face
* Large ears
* Large testicles
* Prominent jaw and forehead
* Flat feet
* Flexible fingers

Question 7

Tay Sachs

Answer 7

Causes
* Variants in the HEXA gene which provide instructions for making one part of the enzyme called beta-hexosaminidase. Beta-hexosaminidase is located in lysosomes which help break down fatty acids called GM2 ganglioside found in cell membranes. As a result, GM” accumulates to toxic levels, particularly in neurons in the central nervous system (CNS). Damage caused by the build up of GM2 ganglioside leads to dysfunction and eventual death of these neurons.
Symptoms
* Slow development
* Weakness of muscles
* Lose previously acquired skills such as rolling and sitting
* Exaggerated startle to loud noises
* Involuntary muscle twitches
* Seizures
* Dysphagia
* Vision and hearing loss
* Intellectual disability
Confirmation tests
* ‘Cherry spot’ in eye exam
* Hexosaminidase A enzyme test
- Infantile onset Tay-Sachs have absent or nearly absent Hexosaminidase A enzyme activity
- Juvenile or adult onset Tay-Sachs disease usually have 6 - 15% activity
- Carriers have reduced activity
Testing recommended
Autosomal recessive
Young death
Spot in macular
Ashkenzai Jews have highest carrier rate
CNS degeneration
Hex A deficiency
Storage disorder (lysosomal)

Question 8

Cystic Fibrosis

Answer 8

Causes
* Mutations in the CTFR gene cause cystic fibrosis (CF) which provides instructions for making a channel that transports negatively charged particles called chloride ions in and out of cells. Mutations in the CTFR gene disrupt the function of chloride channels preventing them from regulating the flow of chloride ions and water across cell membranes. As a result, cells that line the passageways of the lungs, pancreas and other organs to produce mucus that is unusually sticky and thick.
Symptoms
* Slow to gain weight
* Small for age
* Always seems to have a cold
* Recurrent chest infections
* Bulky bowel movements
* Prevalence: 1 in 2,500 and Carrier rate: 1 in 25
Cystic Fibrosis Transmembrane Conductor (CFTR)
* CFTR is a member of the ATP-Binding Cassette (ABC) transporter family that functions as a gated chloride channel located in the mucus membranes. Defects in this channel result in the mucus having less osmotic potential and so is thicker.
Cystic Fibrosis Diagnosis
* Heel prick test: tests for raised levels of immunoreactive trypsinogen within the blood.
* Sweat test: tests for chloride levels
- Below 30mmol/L: CF is unlikely
- Between 30 - 59mmol/L: CF is possible and additional testing is needed
- 60mmol/L or above: CF is likely to be diagnosed
* Confirmation via genetic screening
Genetic variation in the CFTR gene
* Over 1700 disease causing mutations have been found for CF. The mutations are grouped on their impact of CFTR and its level of remaining function so the class of the mutation is also linked to the severity of the disorder.
Delta F508
* The most common mutation in the gene associated with CF causes deletion of phenylalanine at codon 508.
Treatment
* Medicines for lng problems (antibiotics to prevent and treat chest infections, mucus thinner, bronchodialators, steroid medicine)
* Exercise
* Airway clearance techniques
* Dietary and nutritional advice
* Lung transplants

Question 9

Sickle Cell Anaemia

Answer 9

Characteristics
* An autosomal recessive disorder
* A group of disorders that affects the haemoglobin. People with this disorder have atypical haemoglobin called haemoglobin S which distorts into a sickle shape.
* Anaemia (which also causes fatigue, shortness of breath, delayed growth and development and jaundice)
* Repeated infections
* Periodic pain (which occur due to sickled cells get stuck in narrow blood vessels which can lead to deprive organs of oxygen which leads to organ failure)
* Pulmonary hypertension (high blood pressure in blood vessels that supply tyhe lungs which leads to heart failure)
Frequency
* Most common amongst people whose ancestors are from Africa
Causes
* Mutations in the HBB gene which provides instructions for making the beta haemoglobin gene.
* Mutated forms of HBB lead to HbS, HbC and HbE
* Low levels of beta haemoglobin lead to beta thalassaemia
* In people with sickle cell disease at least one of the beta haemoglobin subunits is replaced with haemoglobin S
* In sickle cell anaemia, also called homozygous sickle cell disease, the most common form of sickle cell, haemoglobin S replaces both beta globin chains
* People with haemoglobin sickle C have HbSC instead of beta globin
Genetics
* At least 1 mutation has to be p.Glu6Val. The normal codon is GAG for Glutamate but the sickle cell codon is GUG for Valine.
Glutamate - polar, hydrophillic, negatively charged
Valine - aliphatic, hydrophobic, neutral
Environmental triggers for a sickle cell crisis
* Sudden change in temperature
* Strenuous exercise
* Dehydration
* Infections
* Stress
* High altitudes
* Alcohol
* Smoking
* Pregnancy
* Other medical conditions

Question 10

Haemoglobinopathies

Answer 10

A group of disorders that is inherited in which there is abnormal production or structure of the haemoglobin molecules eg. sickle cell disease
Hb Hyde Park
* A rare cause of cyanosis (lack of oxygen in blood circulation) which causes a bluish discolouration
* Oxidised haem iron is resistant to methemglobin reductase.
Hb Kempsey
* Hb keeps its high affinity structure
* Less oxygen available to tissue
* Autosomal dominant
* Polycythaemia in heterozygotes which is high concentration of haemoglobin in blood
Hb Hammersmith
* Unstable so has a decreased affinity of oxygen
* Found that haemoglobin is precipitated in the tubules of damaged kidneys excreting either acid/alkaline urine
* Haemolysis (destruction of RBC’s)
* Low oxygen affinity
* Autosomal dominant
Heinz Bodies
* Erythrocyte structures composed of precipitated denatured haemoglobin
Bite Cells
* RBC’s with irregular membranes as a result of removal of denatured hameoglobin by macrophages in the spleen
Alpha-Thalassaemia
* An inherited blood disorder in which the body doesn’t make much alpha globin
HbH Disease
* Moderately severe haemolytic anaemia
* HbH tetramers have a high affinity for oxygen
* Highly unstable, precipitating as toxic Heinx Bodies
Hydrops Fetalis
* Edema (severe swelling in newborn baby)

Question 11

Alkapetonuria (AKU)

Answer 11

Characteristics
* Autosomal recessive
* An inherited condition that causes urine to turn black when exposed to air.
* Onchrosis, a build up of dark pigment in connective tissue such as cartilage and skin.
* People with AKU usually develop arthritis, particularly in the spine and large joints
* Kidney stones, prostate stones and heart problems
Causes of AKU
* Mutations in the homogentisate 1,2 dioxygenase (HGD gene) cause AKU which provide instructions for making an enzyme called homogentisate oxidase which helps break down the amino acid phenylalanine and tyrosine. As a result, homogentisic acid accumulates in the body and is deposited within connective tissues which causes cartilage and skin to darken over time. Over time, a build up of this substance in the joints leads to arthritis. Homogentisic acid is also excreted in urine making the urine turn dark when exposed to air.

Question 12

Phenylketonuria (PKU)

Answer 12

Increases the level of phenylalaline (obtained through diet) in the blood.
Symptoms
* Behavioural and intellectual disabilities
* Seizures
* Delayed development
* Psychiatric problems
* Musty odour
* Lighter hair and skin
* Likely to have skin disorders such as eczema
* Babies born to mothers who have PKU have a significantly higher risk of intellectual disability as they are exposed to high phenylalanine before birth. As well as having a low birth weight and grow slower in comparison to other children.
* Heart defects and heart problems
* Abnormally small head size
Causes
* Mutations in the PAH gene
* PAH gene encodes for making an enzyme called phenylalanine hydroxylase which converts phenylalanine to other important compounds in the body
* Autosomal recessive

Question 13

Tyrosinase Negative Occulocutaneous Albunism

Answer 13

• An autosomal recessive condition affecting melanin production
• Different levels have different variants of activity
• About 1 in 20,000 worldwide
  Symptoms
• Lack of pigment in hair, skin and irises
• Light sensitivity
• Vision issues
• Increased risk of skin cancer

Question 14

Linked disorders: occulocutaneous albinism

Answer 14

• Type 1 - FRY gene - Very pale skin, white hair and light coloured irises
• Type 2 - OCA2 gene - Pale skin, light coloured irises, hair may be yellow/light brown
• Type 3 - TRYP1 gene - Affects dark skinned people, reddish brown skin, ginger/red hair, hazel/brown irises
• Type 4 - SLC45A2 gene - Pale skin, light coloured irises and hair may be light yellow, blonde or light brown

Question 15

Tyrosinemia Type 1

Answer 15

• Genetic disorder characterised by the disruptions in the multistep process that breaks down the amino acid tyrosine
• Tyrosinemia type 1 is the most severe form and is characterised by signs and symptoms that develop within the first few months of life
  Symptoms
• Fail to gain weight
• Poor food tolerance which leads to vomiting and diarrhoea
• Yellowing of skin and whites of eyes
• Cabbage like odour
• Increased tendency to bleed
• Kidney and liver failure
• Softening and weakening of bones
• Increased risk of liver cancer
• Changes in mental state
• Reduced sensation in arms and legs
• Abdominal pain
• Respiratory pain/failure
• Children often do not survive past age 10
  Causes
• Mutations in the FAH, TAT and HPD gene cause type 1, 2 and 3
• In the liver, enzymes break down tyrosine in a five step process resulting in molecules that are excreted by the kidneys or used to produce enegy or make other substances in the body
• The FAH gene provides instructions for the fumarylacetoacetate hydrolase enzyme which is responsible for the final step of tyrosine breakdown.
• The enzyme produced from the TAT gene called tyrosine aminotransferase is involved at the first step of the process
• The HPD gene provides instructions for making the 4-hydroxylphenylpyruvatedeoxygenase enzyme which is responsible for the second step
  Succinylacetone levels are a good diagnostic indicator of Tyrosinemia type 1
  Treatment
• Reduce intake of phenylalanine and tyrosine
• Dramatic improvement of prognosis following treatment of the tyrosine catabolism

Question 16

Tyrosinemia Type 2

Answer 16

• Can effect the skin, eyes and mental development
• Signs and symptoms begin in early childhoodand include eye pain and redness, excessive tearing, abnormal sensitivity to light and thick, painful skin on the palms of their hands

Question 17

Tyrosinemia Type 3

Answer 17

• Seizures
• Intellectual disabiltiy
• Loss of balance and coordination
• Rarest if three types

Question 18

Retinitis Pigmentosa

Answer 18

Characteristics
* Group of related eye disorders that cause progressive vision loss
* The disorders affect the retina which is the layer of light-sensitive tissue at the back of the eye
* In people with retinitis pigmentosa, the cells of the retina degenerate gradually meaning there is vision loss
Symptoms
* Loss of night vision
* Blind spots develop in peripheral vision which merge overtime to produce tunnel vision progressing to affect central vision making the individual legally blind
* When the disease occurs by itself it is known as non-syndromic
* Less commonly, when retinitis pigmentosa occurs as part of a syndrome that affects other organs and tissues in the body which is described as syndromic, eg. Usher’s Sydrome

Question 19

Usher’s Syndrome

Answer 19

Characteristics
* Autosomal recessive inheritance
* A condition that is characterised by partial or total hearing loss that worsens over time as well as vision loss.
* There are three major types of Usher’s Syndrome that are characterised by the severity of hearing loss, the presence or absence of balance problems and the age at which symptoms occur
Symptoms
Usher Syndrome Type I
* Born with severe to profound hearing loss
* Worsening vision loss caused by RP becomes apparent in childhood
* Type I causes abnormalities of the vestibular system in which helps maintain the body’s balance
Usher Syndrome Type II
* Vision and hearing loss begins in adolescence and childhood
* Hearing loss ranges from mild to severe
* Type II does not associate itself with vestibular abnormalities
Usher Syndrome Type III
* Experience vision and hearing loss later in life
* Type III id associated with normal hearing at birth and loss begins during late childhood or adolescence
* By middle age, hearing loss is profound
Causes
* Mutations in at least six genes cause Usher Syndrome Type I
* The genes associated with Usher Syndrome provide instructions for making proteins in normal hearing, balance and vision
* In the inner ear, these proteins are involved in the development and function of specialised cells called hair cells which help transmit signals and sound to the inner brain
* In the retina, the proteins contribute to the maintenance of light-sensing cells called rod receptors and cone photoreceptors

Question 20

Bardet-Biedl Syndrome

Answer 20

Characteristics
* Combines retinitis pigmentosa with variably associated obesity, cognitive impairment, polydactyly, hypogenitalism and renal disease
* Learning problems
* Most affected males produce reduced amounts of sex hormones
* Kidney abnormalities
* Distinctive facial features
* Dental abnormalities
* Loss of sense of smell
Causes
* Can result in a mutation of 14 different genes, called BBS genes
* BBS genes play a critical role in cell structures called cillia
* The proteins produced by BBS genes playa role in the maintenance and function of cilia
* Defects in the cilia disrupt important chemical signalling pathways during development and lead to abnormalities of sensory perception
* About 25% of cases are as a result of mutations in the BBS1 gene
* About 20% of cases are caused by the BBS10 gene
* In affected individuals who have mutations in one of the BBS genes, mutations in additional genes may be caused or modifying the course of the disorder
Non-syndromic retinitis pigmentosa (RP) overlap with related disorders
Enhanced Cone Syndrome
* Cataract
* Haemaralopi
* Day blindness
* Macular edema
Macular Dystrophy
* Vitelliform - like macular lesions
* Colour vision defect
* Abnormal colour vision
* Light eye colour
* Visual field defect
** Leber Congenital Amaurosis**
* Photophobia
* Nysytgnus
* Cataract
* Cross eyed
* Enophthalmes
* Abnormal retinal pigment
* Extreme farsightedness
* Generally non-progressive

Question 21

NARP

Answer 21

Characteristics
* Mainly effects the nervous system
* Begins in childhood/early adulthood
* People experience numbness, tingling or pain in the arms and legs, muscle weakness and problems with coordination
* Dementia
* Seizures
* Hearing loss
* Abnormalities of electrical signals that effect the heartbeat
Causes
* Caused by mutations in the MT-ATP6 gene which is contained in mitochondrial DNA. MT-ATP6 gene provides instructions for making a protein that is essential for normal mitochondrial function. MT-ATP6 protein forms a subunit of an enzyme called ATP synthase which is responsible for the last step in ATP production. When there is a mutation, the structure of ATP synthase as well as the funtion is reduced so reduces the ability of the mitochondria to make ATP.
Inheritance
* Mitochondrial pattern also known as maternal inheritance
* Applies to genes contained in mtDNA becuase egg cells contribute to mitochondria

Question 22

Marfan Syndrome

Answer 22

Characteristics
* Disorder that affects the connective tissue in many parts of the body which provides strength and flexibility to structures such as bones, ligaments, muscles, blood vessels and heart valves
Symptoms
* Causes abnormalities in heart, blood vessels, eyes, bones and joints
* Vision problems caused by a dislocated lense (ectopia lentis)
* Defects in the large blood vessel that distributes blood from the heart to the rest of the body (aorta)
* The aorta can weaken and stretch which can lead to a bulge in the vessel wall (aneurysm)
* Stretching of the aorta can cause the aortic valve to leak which can lead to a sudden tearing of the layers in the aortic wall (aortic dissection)
* Additional heart problems eg. leak in the valve that connects two of the four chambers (mitral valve prolapse) or the valve that regulates blood flow from the heart into the aorta (aortic valve regurgitation)
* Tall and slender, long fingers and toes (aranodactyly), loose joints and an arm span that exceeds height
* Long and narrow face, crowded teeth, curved spine, stretch marks not related to weight gain or loss, sunken or pertruding chest
* Abnormal accumulation of air in the chest which will result in the collapse of a lung
* The dura (membrane surrounding the brain) can be abnormally enlarged (dural ectasia) which can cause pain in the back, abdomen and legs or head
* Near sightedness (myopia)
* Clouding of the lens (cataract)
* Glaucoma
* Symptoms become apparent between infancy and adulthood
Causes
* Mutations in the FBN1 gene which provides instructions for making a protein called the Fibrillin-1 which binds to other Fibrillin-1 proteins to form thread-like structures called microfibrils which become part of the fibres to provide strength and flexibility to connective tissue. Additionally, microfibrils bind to molecules called growth factors and release them at various points to control the growth and repair of tissues and organs throughout the body. A mutation in the FBN1 gene can reduce the amount of functional Fibrillin-1 that is available to form microfibrils which leads to decreased microfibril formation, meaning they cannot bind to growth factors so excess growth factors are available and elasticity in many tissues is decreased leading to overgrowth and instability of tissues in marfan syndrome.
Inheritance
* Autosomal dominant
* 25% of cases result from a new mutation in the FBN1 gene

Question 23

Parkinson’s Disease

Answer 23

• Common adult onset neurodegenrative disorder
• 2 - 3% of people aged 65 and over are affected
• More common in men
• 5 - 10% of cases are heriditable forms, the rest are sporadic
  Features
• Resting tremor
• Slowed movement (bradykinesia)
• Muscle rigidity
• Impaired posture and balance
  Epidemiology
  (Epidemiology is the distribution within a population)
• Incidence is high within Israel possibly due to the high prevalence of the incompletely penetrant LRRK2 and GBA variants in Ashkenzai Jews
• Prevalence high in Inuit
• Difference in prevalence between genders is lower in Japan
  Pathogenesis and aetiology
  (Pathogenesis is the likelihood of the mutation to cause disease and aetiology is the set of causes)
• Neuronal loss in specific areas of the substantia nigira which results in reduced dopamine production
• Intracellular accumulation of the protein alpha-synuclein (Lewy bodies)
  Monogenic Forms
• 2 - 5% of Parkinson’s disease cases are monogenic
• Mutations that occur in a single gene

Question 24

Dementia and Alzheimer’s

Answer 24

• 850,000 people living with dementia in the UK
• Alzheimer disease is the most common form of dementia (approximately 2/3)
• Other forms include:
  1. Vascular dementia
  2. Dementia from Parkinson’s Disease
  3. Dementia with Lewy bodies
  4. Frontotemporal dementias
  5. Mixed dementia
  Exposome
• Diet
• Drugs
• Psychology
• Physical health
• Diet
• Social network
  Alzheimer’s
• Characterised by debilitating and progressive episodic memory loss
• The neuropathologic hallmarks of the AD brain include an abundance of senile plaques largely composed of beta-amyloid deposits and neurofibrillary tangles made up of Tau protein
• Alzheimer’s genetics
• Early onset cases caused by these genes (Causes Alzheimer’s) (PSEN1, PSEN2 and APP)
• Around 2% of the population have 2 copies, making them 8 times more likely to develop the disease (Risk of Alzheimer’s) (APOE4)
• 1 in 4 people have 1 copy so are around 3 times more likely (Risk of Alzheimer’s) (APOE4)
• 0.3% have risk variant in TREM2 making them 3 times more likely (Risk of Alzheimer’s) (TREM2)
• Most common are MS4A, CR1, PICAIM, BIN1, CLV, CD2AP, CD33, EPHA1, ABCA7)

Question 25

Prader Willi Syndrome

Answer 25

Prader-Willi syndrome and Angelmann syndrome are both linked to the same imprinted chromosome 15 region (examples of genomic imprinting)
Symptoms
* Weak muscle tone (hypotonia)
* Feeding difficulties
* Poor growth
* Delayed development
* Extreme hunger
* Chronic overeating (hyperphagia)
* Obesity
* Type 2 diabetes
* Intellectual impairment
* Behavioural problems
* Sleep abnornmalities
* Distinctive facial features
1. narrow forehead
2. almond shaped eyes
3. triangular mouth
4. short stature
5. small hands and feet
* Light coloured hair
* Undeveloped genitals
Causes
* Loss of function of genes on chromosome 15
* Segment of chromosome 15 on the paternal gene is missing and the maternal genes turned off (inactive) is the reason for approximately 75% of cases
* The other 25% is caused by two copies of chromosome 15 being inherited from the mother (maternal uniparental disomy)
Inheritance
* Sporadic

Question 26

Angelmann Syndrome

Answer 26

• Primarily affects the nervous system
  Features
• Delayed development
• Intellectual disability
• Speech impairment
• Ataxia
• Epilepsy
• Microephaly
• Happy and excitable demeanour
• Hyperactivity and short attention span
• Difficult sleeping
• Coarse facial features
• Fair skin, light coloured hair
• Curvuture of spine
  Causes
• Loss of function of a gene called UBE3A
• People normally inherit one copy from each parent, both turned on. However, people affected from Aneglmann syndrome only have the maternal copy activated.
• In 70% of cases, it occurs when a segment of the maternal chromosome 15 containing this gene is deleted
• In other cases, 10 - 20% of cases of Angelmann syndrome is caused by a variant in the maternal copy of of the UBE3A gene
• In a small percentage of cases, Angelmann syndrome is results from inheriting two copies, one from each parent, known as uniparental disomy
  Inheritance
• Sporadic
  Summary of Angelmann Syndrome and Prader Willi Syndrome
• Both occur due to the loss of the chromosomal region
• Contains paternally expressed SNRPN and NDN and maternally expressed UBE3A
• Paternal inheritance of a deletion of this region = Prader Willi Syndrome
• Maternal inheritance of a deletion of this region = Angelmann Syndrome

Question 27

Beckwith - Weidemann Syndrome (IGF2 imprinting disease)

Answer 27

Symptoms
* Overgrown syndrome (macrosomia)
* Asymmetric appearance (hemihyperplasia)
* Opening in the wall of the abdomen (omphalocele) allows abdominal organs to pertrude through belly button
* Abnormally large tongue (macroglessia)
* Large abdominal organs
* Low blood sugar (hypoglycemia)

Question 28

MERFF Syndrome

Answer 28

• Myoclonus Epilepsy with Ragged Red Fibres
• Very rare mitochondrial disease (1 in 5,000 people)
• Myoclonus is a sudden, uncontrolled muscle spasm
• Abnormal muscle cells stained with the Gomori trichrome are present in muscles and appear as ragged red fibres under a microscope due to accumulation of abnormal mitochondria near the plasma membrane of the muscle fibre.
• The disease begins in childhood and affects nerves and skeletal muscles. Other symptoms include short stature, atrophy of the optic nerve, hearing loss, cardiomyopathy and abnormal sensation from nerve damage (peripheral neuropathy) and impaired coordination of movements (ataxia), seizures and the development of dementia.

Question 29

Huntington’s Disease

Answer 29

Huntington’s Disease is a progressive neurological disorder that causes uncontrolled movements, emotional changes and loss of cognitive ability.
Adult onset Huntington’s Disease
* Most common form
* Appears in a person in early 30’s or 40’s
* Irritability
* Depression
* Small involuntary movements
* Poor co-ordination
* Trouble learning new information and making decisions
* Involuntary jerking or twitching (chorea) which becomes more pronounced as the disease progresses
* Difficulty walking, speaking and swallowing
* Experience changes in personality
* Decline in thinking and reasoning
* Live for about 15 - 20 years after diagnosis
Juvenile form of Huntington’s Disease
* Movement problems
* Mental and emotional changes
* Slow movements
* Clumsiness
* Frequent falls
* Rigidity
* Slurred speech
* Drooling
* Impaired thinking and reasoning abilities
* Seizures
* Tends to progress quicker than the adult-onset form
* Affected individuals tend to live for about 10 - 15 years after symptoms appear
Frequency
* 3 to 7 per 100,000 people of the European ancestry
* Less common in individuals of Chinese, Japanese and African descent
Causes
* Caused by mutations in the HTT gene which provides instructions for a protein called Huntington which appears to play an important role in neurons in the brain
* The HTT mutation that causes Huntington Disease involves a DNA segment known as a CAG trinucleotide repeat. Normally, the CAG segment repeat is repeated 10 - 35 times within the gene. In people with Huntington Disease, the CAG segment is repeated 36 to 120 times. People with 36 to 39 CAG repeats may or may not develop the signs and symptoms of Huntington Disease while people with 40 or more repeats almost always develop the disorder. An increase in the size of the CAG protein segment leads to the production of an abnormally long version of the Huntington protein. The elongated protein is cut into smaller, toxic fragments that bind together and accumulate in neurons, disrupting the normal functions of the cells. The dysfunction and eventual death of neurons in certain areas of the brain underlie the signs and symptoms of Huntington’s Disease.
Inheritance
* Autosomal dominant pattern
* As the altered HTT gene is passed from one generation to the next, the size of the CAG repeat is often increased in size. A larger number of repeats is usually associated with an earlier onset of signs and symptoms.

Question 30

Familial Hypercholesterolemia (FH)

Answer 30

• FH is caused by mutations in the genes associated with lipid metabolism
• Autosomal dominant disorder characterised by deficiency or defective function of LDLR
• Affects 1 in 500 people in the UK
• Clinical features: Very high levels of LDL, early onset of CVD
• Symptoms: Yellow cholesterol deposits around eyes and tendons (Xanthomas)
• Around 85% of people with FH are undiagnosed
• Treatment for heterozygotes is statins, the treatment for homozygotes is statins and LDL
  ARMS PCR Kit
• The Tenpel ARMS PCR Kit is currently used in the UK to screen for the 20 most common FH causing mutations
• This will detect known mutations only, as the primers are designed to amplify common FH variants
  FH Cascade Screening
• Cascade screening is used to identify people at risk for a genetic condition by a process of family tracing
• FH has a high prevalence amongst family members, with 50% of relatives of heterozygotes affected
• Once a patient (the index case) has been identified as having an FH causing mutation, their 1st and 2nd degree relatives may also be called in for screening
• This will consist of serum LDL measurement and genetic testing
• NICE review showed that the cascade process significantly reduces the morbidity and mortality in FH heterozygotes with appropriate statin treatment