X-LINKED AND MITOCHONDRIAL DISORDERS

Question 1

• Colour vision deficiency

Answer 1

• Common X-linked disorder group
• Red-green defects are most common in Northern European ancestry
  
  • 1 in 12 males
  • 1 in 200 females
• OPM1LW (Yellow/orange) and OPN1MW (Yellow/green detection) are also located on the X chromosome
• Males more affected than females
• Male affected - carrier daughter - affected son (can skip a generation)
• Origin
  
  • X chromosomes have red opsin gene and green opsin gene
  • Misalignment in crossing over causes only one or the other gene to be left on the chromosome, with the other three on the other chromosome
    
    • This results in a 75% chance in a normal child
    • Males have a 50% chance of having colour deficiency

Question 2

• Hypophosphatemic rickets

Answer 2

• Low levels of phosphate in the blood (hypophosphatemia) leads to a lower than normal amount of Ca2+ being deposited in bones
  
  • Causes bones to weaken and become softer
  • Individuals become Vitamin D treatment resistant
• May cause bowing of the legs, pigeon-breast deformity, curvature of the spine, increased tendency for bones to break easily, squaring of and flattening of the skull
• Teeth take longer to appear, and the enamel is softer
• Affects about 1 in 20,000 newborns
• Mutations in the PHEX gene, which are responsible for X-linked dominant hypophosphatemic rickets which is more frequent
  
  • The gene encodes about 749 amino-acid polypeptides with significant homology to the membrane-bound zinc metallopeptidase family
  • Their role in Vitamin D synthesis or phosphate metabolism is currently unknown
• Ratio of males to females is 16:20 (About 1:1)
  
  • Unlike autosomal dominant traits
    
    • Ratio of affected females is about 2:1 - women have twice the risk as they inherit two X chromosomes
  • However, males tend to be more severely affected than females

Question 3

• Duchenne muscular dystrophy (DMD)

Answer 3

• Muscular dystrophies are a group of genetic conditions characterized by progressive muscle weakness and wasting (atrophy)
• Primarily affect skeletal muscles which are used for movement and cardiac muscle
• Occurs almost exclusively in males
• Clinical features - young boys use “Gower’s manoeuvre” to rise from the floor
• Boys with DMD 1 in 3500-5000 have apparently normal muscles up to the age of 1-3 years
  
  • Milestones are delayed (i.e. learn to stand and walk later, speech development may be slow)
  • Weakness progresses - first in proximal pelvic girdle muscles, then shoulder girdle, then face
  • Hypertrophy of calf muscles (pseudohypertrophy - due to deposition of fat and fibrous tissue)
  • Lead to most boys having to use wheelchairs by 10-12 and death by 20
• Most common cause of death is cardiac muscle failure/respiratory failure
• DMD therapy
  
  • Exon skipping

Question 4

• Becker muscular dystrophy (BMD)

Answer 4

• Milder form of duchenne muscular dystrophy (DMD)
• Symptoms onset in 2nd decade of life, inability to walk occurs 20 years after onset of symptoms
• Cardiac involvement in BMD often does not correlate with the severity of skeletal muscle weakness and may be the presenting symptom in adolescence
• The gene defect of BMD and DMD lies in the DMD gene that encodes for the dystrophin protein
• DMD is the largest known gene in the human genome - 2.3 mega-bases with 79 exons
  
  • DMD is over 10 times larger than the factor VIII gene (haemophilia), and over a hundred times larger that the β-globin gene (beta-thalassemia)
  • DMD gene is a critical structural protein
  • Dystrophin is located under the cell membrane in striated muscle (Thin sheath that surrounds muscle cells)
  • Dystrophin, lying under the fibre membrane, attaches to a small cluster of other muscle proteins and is part of a complex (DSC) that spans the membrane and attaches to the tissue outside the fibre - the extracellular matrix
• Dystrophin plays a role in preventing damage to the membrane during muscle fibre contraction, although the details of how it does this are not very clear
• The leading hypothesis suggests a structural role for dystrophin - linking the extracellular matrix, via laminin and the dystroglycans, to cortical actin, to provide strength

Question 5

• Haemophilia

Answer 5

• X-linked recessive disorder characterized by the inability to properly form blood clots
• Most common forms are associated with mutations in the F8 gene - responsible for making coagulating factor VIII (80% of cases and causes severe problems = Haemophilia A)
  
  • Haemophilia A - 1 in 4-5000 males
• Mutations in F9 gene which is responsible for making coagulation factor IX (20% with mild problems = Haemophilia B)
  
  • Haemophilia B - 1 in 20,000 males
• Until recently, it was untreatable and very few survived to reproductive age as any small cut/haematoma could be fatal (even minor bruising)
• Blood clotting cascade
  
  • Severity of haemophilia depends on where the blood clotting pathway (Coagulation cascade) is affected
• Historically treated with blood transfusions and infusions of blood derived from anti-haemophilic factor
  
  • However, such treatment is very expensive and involves much risk of contracting a number of serious diseases, such as AIDS and hepatitis
• Recently, recombinant clotting factors (protein made in cells in vitro using recombinant DNA technology) has alleviated this problem

Question 6

• Kennedy disease

Answer 6

• Progressive muscular atrophy disorder of specialised nerve cells in the spinal cord that control muscle movement (Motor neurons)
  
  • Also known as spinal and bulbar muscular atrophy
• Bulbar muscles are specific muscles in the face and throat that assist with swallowing and speech
• Caused by mutation of the AR gene - leads to expansion of CAG triplet repeats in the androgen receptor protein (>35 CAG repeats)
• Most resources - X-linked recessive
• Mainly affects males with some being infertile due to involvement of androgen receptor
• Age of onset is in later adulthood (30-50s) with 1 in 150,000 males being affected
• Often misdiagnosed as amyotrophic lateral sclerosis (ALS) - also known as Lou Gehrig’s disease after famous American Baseball player
• After 1-2 decades of symptoms, most affected individuals have difficulty climbing stairs
  
  • With time, atrophy of the proximal and distal musculature becomes evident
  • About 1/3 affect individuals require a wheelchair 20 years after the onset of symptoms
  • Normal life expectancy, but quality of life is severely affected
  • Heterozygote females are usually asymptomatic -protected by second X-chromosome and random X-inactivation (Barr bodies)
  • Homozygous females - tend to have more mild phenotypes with muscle cramps and occasional tremors
    
    • Thought to be more mild due to lower androgen level in females

Question 7

• Mitochondrial diseases

Answer 7

• Mitochondrial mutations and diseases
  
  • Disease due to mutations in genes that impair protein synthesis
  • Mutated genes that encode respiratory chain proteins
  • Some mitochondrial disease names are named after the symptoms (MELAS) as they have not been fully characterized yet
  • Problem - mutations in more than 1 loci can lead to the same mitochondrial disease
    
    • Multiple mitochondria with different genomes
    • Therefore, very difficult to diagnose mitochondrial disorders
• Mitochondrial pedigrees
  
  • All children of an affected female but none of the children of an affected male will inherit the disease
  • Some females with the disease have both normal and diseased mitochondria
  • Mitochondrial DNA is only inherited from the mother

Question 8

• Leigh disease

Answer 8

• Can result from several different types of gene-determined metabolic defects
• More than 75 genes (majority nuclear) can lead to leigh disease
  
  • Most common mtDNA mutation is in the mitochondrial gene (MTATP6) encoding ATPase6 - causing deficiencies in ATP production and OXPHOS
  • Other enzymatic deficiencies are also referred to as Leigh disease and exhibit similar phenotypes
  • The most common treatment for Leigh disease is the administration of thiamine (Vitamin B1) - if deficiency of pyruvate dehydrogenase is proven/suspected
  • Oral sodium bicarbonate or sodium citrate may also be prescribed for management of lactic acidosis
  • Genetic counselling is complex for mitochondrial disease since it can be uncertain what percentage of the affected mitochondria will be partitioned into a given ova