Single Gene Disorders: Huntington’s Disease

Question 1

Describe the pathophysiology of Huntington’s disease [2]

Answer 1

HD is caused by an abnormal expansion of the CAG trinucleotide in the huntingtin gene (located on chromosome 4).

Results in degeneration of cholinergic and GABAergic neurons in the striatum of the basal ganglia

The number of repeats of CAG is related to onset of disease (more = earlier)

Question 2

Describe the features of HD [6]

Answer 2

• chorea
• personality changes (e.g. irritability, apathy, depression) and intellectual impairment
• dystonia
• saccadic eye movements
• Rigidity (increased resistance to the passive movement of a joint)
• Dysarthria (speech difficulties)
• Dysphagia (swallowing difficulties)

Question 3

TOM TIP: Anticipation is a common concept tested in exams and worth remembering with Huntington’s.

What does it mean [1]

Answer 3

Anticipation is a feature of trinucleotide repeat disorders, where successive generations have more repeats in the gene, resulting in:

• Earlier age of onset
• Increased severity of disease

Question 4

What is important to note about genetic testing of HD? [1]

Answer 4

They need to be 18 before they can decide whether to get tested.

Your job is to provide information for the patient to make an informed decision for themselves, not to advise them whether to have a test or not. The outcome is usually that the patient will think about it further and return if they have further questions.

Question 5

What are two main causes of death from HD? [2]

Answer 5

Death is often due to aspiration pneumonia or suicide

Question 6

Describe the pathophysiology of Fragile-X syndrome

Answer 6

Fragile X syndrome is caused by a mutation in the FMR1 (fragile X mental retardation 1) gene on the X chromosome.

The FMR1 gene codes for the fragile X mental retardation protein, which plays a role in cognitive development in the brain.

Question 7

Describe the inheritence of Fragile-X mental retardation [1]

Answer 7

It is X-linked dominant

Males are always affected, but females can vary in how much they are affected.
This is because females have a spare normal copy of the FMR1 gene on their other X chromosome.

Question 8

Describe the features of Fragile X syndrome in males and females

Answer 8

Features in males
* learning difficulties
* large low set ears, long thin face, high arched palate
* macroorchidism
* hypotonia
* autism is more common
* mitral valve prolapse

Features in females (who have one fragile chromosome and one normal X chromosome)
* range from normal to mild

Question 9

What is the inheritence pattern of Hypophosphatamic rickets? [1]

Answer 9

Hereditary hypophosphataemic rickets.
- The most common form is x-linked dominant, however it also has other modes of inheritance.
- There is a rare form of rickets caused by genetic defects that result in low phosphate in the blood

Question 10

Describe the pathophysiology of X-linked dominant-Hypophosphatamic rickets [3]

Answer 10

• Suggested that the phosphate regulating endopeptidase X-linked (PHEX) enzyme regulates fibroblast growth factor 23 (FGF23).
• This protein normally inhibits the kidneys’ ability to reabsorb phosphate into the bloodstream.
• There is an increase of FGF23 in patients but no direct link yet between the proteins.

Question 11

Describe the genetic risk factors for alzheimers disease derived from Apolipoprotein E [3]

Answer 11

ApoE has three alleles:
- e2: protective of risk of AD
- e3: neutral towards risk of AD
- e4: increases risk (if have both - risk is much bigger)

Question 12

Which single genes, that if mutated, are definitely going to increase the liklihood of having AD? [3]

Answer 12

APP
PSEN1
PSEN 2

Question 13

Describe how APP and PSEN genes contribute to AD pathophysiology [2]

Answer 13

APP: when cleaved by B & Y secretases get ABP - accumulates to cause amyloid plaques in brain

PSEN [1&2] function as part of the complex the cleaves in the y site - so if have hyperfunction of PSEN then causes AD

Question 14

Apoprotein E allele E4 - encodes a [] transport protein

Answer 14

apoprotein E allele E4 - encodes a cholesterol transport protein

Question 15

Describe how you can get AD through aneuploidy

Answer 15

Aneuploidy: gain or loss of chromosome arms

Down’s syndrome - trisomy 21 is APP gene is located on chr 21

Question 16

Describe APP duplication in AD [1]

Answer 16

People without DS (and three genes of APP), aquire duplication of APP - get 100% penetrance of AD, and develops at around 40 yrs

Question 17

Name a gene that has been found to be a suppressor gene for AD [1]

Answer 17

BACE2

Question 18

What are the three modes of inheritence for Down’s Syndrome

Answer 18

In rare cases there are inherited risks of DS:
- Translocation of Chr 21 & 14 if children are born with

Question 19

Which are the only three viable autosome aneuploidies? [3]

Answer 19

Trisomy 21 (Down’s syndrome)
Trisomy 13 (Patau’s syndrome)
Trisomy 18 (Edwards syndrome)

Question 20

Describe the features of:
* Trisomy 13 (Patau’s syndrome)
* Trisomy 18 (Edwards syndrome)

Answer 20

Trisomy 13 (Patau’s syndrome):
* Microcephalic, small eyes
* Cleft lip/palate
* Polydactyly
* Scalp lesions

Trisomy 18 (Edwards syndrome):
* Micrognathia
* Low-set ears
* Rocker bottom feet
* Overlapping of fingers

Question 21

47, XXY refers to which sex chromosome aneuploidy? [1]

Describe the features of this syndrome [+]

Answer 21

47, XXY: Klinefelter syndrome
* Taller height
* Wider hips
* Gynaecomastia
* Weaker muscles
* Small testicles
* Reduced libido
* Shyness
* Infertility
* Subtle learning difficulties (particularly affecting speech and language)

Question 22

45 XO refers to which sex chromosome aneuploidy? [1]

Describe the features of this syndrome [+]

Answer 22

Turner syndrome occurs when a female has a single X chromosome, making them 45 XO.

• Short stature
• Webbed neck
• High arching palate
• Downward sloping eyes with ptosis
• Broad chest with widely spaced nipples
• Cubitus valgus
• Underdeveloped ovaries with reduced function
• Late or incomplete puberty
• Most women are infertile
• Cubitus valgus refers to an abnormal feature of the elbow. When the arm is extended downwards with the palms facing forward, the angle of the forearm at the elbow is exaggerated, angled away from the body.

TOM TIP: The three classic features to remember and look out for in exams are short stature, webbed neck and widely spaced nipples.

Question 23

Describe the pathophysiology of Rieger syndrome [1]

Answer 23

A deletion of REIG gene from chromosome 4

When gene gets moved to chromosome 12, becomes less active (and acts like a deletion)

Iris of the eye fails to develop - may lead to blindness later in life

Question 24

For acquired uniparental disomy describe the following:
* Type of alteration of genetic material
* The molecular biological consequence
* Which cells are affected
* Patterns of inheritance
* When the disease manifests itself

Answer 24

Acquired uniparental disomy
- involves a change in the genetic material where both copies of a chromosome (or part of a chromosome) are inherited from a single parent instead of one from each parent.
- The molecular consequence of aUPD can vary depending on the specific genes involved and the chromosome affected. However, it can lead to an imbalance in gene dosage, altered gene expression, or loss of heterozygosity, which can result in various genetic disorders or predisposition to certain diseases.
- can affect any cell in the body where the abnormality is present. It can occur during the early development of the embryo or later in life in somatic cells, leading to mosaicism (presence of cells with different genetic makeup).
- typically occurs later in life due to somatic events such as mitotic recombination or nondisjunction during cell division. Therefore, it is not inherited in the classical sense but arises spontaneously during an individual’s lifetime.

Question 25

What is the genetic and pathophysiological features of Tay-Sachs? [3]

Answer 25

**Tay-Sachs disease** is caused by **mutations** in the **HEXA** **gene** located on **chromosome 15** - causes **progressive damage to the nerve cells**, **particularly neurons in the brain**, causing the characteristic neurological symptoms of the disease - Tay-Sachs disease follows an **autosomal recessive pattern of inheritance** - Symptoms of Tay-Sachs disease typically manifest in early infancy, **usually around 3 to 6 months of age.**

Question 26

What is the genetic and pathophysiological features of achondroplasia? [3]

Answer 26

Achondroplasia is an **autosomal dominant disorder** associated with short stature. It is caused by a mutation in the **fibroblast growth factor receptor 3 (FGFR-3)** **gene**. This results in abnormal cartilage giving rise to: * short limbs (rhizomelia) with shortened fingers (brachydactyly) * large head with frontal bossing and narrow foramen magnum * midface hypoplasia with a flattened nasal bridge * 'trident' hands * lumbar lordosis **In most cases (approximately 70%) it occurs as a sporadic mutation**. The main risk factor is advancing parental age at the time of conception. Once present it is typically inherited in an autosomal dominant fashion.

Question 27

What is the genetic and pathophysiological features of ADPKD? [3]

Answer 27

**ADPKD is caused by mutation in either PKD1 or PKD2.** These genes code for the **proteins polycystin 1 and 2, respectively**. Polycystin 1 and 2 are **membrane proteins**, and dysfunction of these proteins results in **aberrant cell signalling pathways**. This results in **disorganised cell growth** and f**luid secretion within the kidneys**, causing fluid accumulation and the formation of **renal cysts.** The consequences of renal cyst formation include: * Increased kidney volume * Compression of normal renal architecture * Interstitial fibrosis * Tubular atrophy * Progressive renal impairment

Question 28

Describe the inheritence pattern of type 1 and 2 ADPKD [2]

Answer 28

ADPKD is divided into two types based on the genetic cause: **Type 1 ADPKD: 85% of cases** * Caused by a mutation in PKD1 on chromosome 16 * Symptoms tend to be **more** **severe** in this type **Type 2 ADPKD: 15% of cases** * Caused by a mutation in PKD2 on chromosome 4 * Symptoms tend to be **less** **severe** in this type

Question 29

**Retinitis pigmentosa** primarily affects **[]** cells in the retina, particularly **[]**, which are responsible for peripheral and night vision.

Answer 29

Retinitis pigmentosa primarily affects **photoreceptor** **cells** in the retina, particularly **rods**, which are responsible for **peripheral and night vision.**

Question 30

What are the features of **Retinitis pigmentosa**? [3]

Answer 30

Features * **night blindness** is often the initial sign * **tunnel vision due to loss of the peripheral retina** (occasionally referred to as funnel vision) * fundoscopy: **black bone spicule-shaped pigmentation in the peripheral retina, mottling of the retinal pigment epithelium**

Question 31

Describe the genetic and pathophysiology of PKU [4]

Answer 31

**Phenylketonuria** (PKU) is an **autosomal recessive condition** caused by a disorder of **phenylalanine** **metabolism**. This is usually due to defect in **phenylalanine hydroxylase**, an enzyme which converts **phenylalanine to tyrosine**. In a small number of cases the underlying defect is a **deficiency of the tetrahydrobiopterin-deficient cofactor** The gene for phenylalanine hydroxylase is located on **chromosome 12**

Question 32

How do patients of PKU present? [5]

Answer 32

The consequences of PKU include: * usually presents by 6 months e.g. with developmental delay * child classically has fair hair and blue eyes * learning difficulties * seizures, typically infantile spasms * eczema * 'musty' odour to urine and sweat