Sex linked disorders can also be called GONOSOMAL  disorders  – from the word gonad – referring to the reproductive cells.

X-linked DOMINANT (generally v. v. rare)

• • Alport syndrome
  • Fragile X syndrome
  • Hypophosphatemic rickets
  • Rett syndrome

• Basic Information
  • • The gene responsible for the disease is located on the X chromosome.
    • Both men and women are affected. The second normal X does not protect the female because the condition is DOMINANT.
    • Affected mothers have a 50% risk of passing the altered gene on to their offspring (regardless of gender).
    • Affected fathers will pass the altered gene to all daughters and no sons.  Yes, all sons will be normal.  The sons get a Y from the dad and a healthy X from a healthy unaffected mum.  

X-linked RECESSIVE

• • Becker muscular dystrophy
  • Congenital night blindness
  • Duchenne Muscular Dystrophy
  • G6PD deficiency
  • Haemophilia A & B
  • Lesch-Nyhan syndrome
  • Red-Green colour blindness 

• Basic Information
  • • The gene for the disease is located on the X chromosome.
    • Men, because they only have the one affected X chromosome, always develop the disease!
    • All daughters who inherit the ONE altered X chromosome are carriers
    • Women are usually carriers and, in rare cases, only affected if both X chromosomes are abnormal.
    • Children of a carrier…
      • • have a 50% probability of inheriting the altered X chromosome.
        • Sons develop the disease, while daughters are carriers.
        • Frequently skips generations.
    • Carrier female + healthy father = probability that they conceive a phenotypically diseased child is 25%.
    • Healthy female + affected father = all male offspring are healthy, because they inherit a Y from the dad and a healthy X from the mum.   Therefore, they cannot pass on the altered gene because they don’t have it.

Non-sex linked disorders can also be called AUTOSOMAL disorders –   from the word somatic.

Autosomal Dominant

• • Achondroplasia
  • Ehlers-Danlos syndrome
  • Familial hypercholesterolaemia
  • Haemochromatosis
  • HOCM
  • Huntingtons
  • Marfan syndrome
  • Neurofibromatosis (types 1 and 2)
  • Polycystic Disease in Children
  • von Hippel-Lindau disease

• Basic Information
  • • Leads to disease even if only one of the pair of chromosomes is altered.
    • If one parent is affected, every child has a 50% risk of inheriting the disease.
    • Autosomal dominant disorders often vary in their expressivity.

Autosomal Recessive

• • Cystic Fibrosis
  • Haemochomatosis
  • Phenylketonuria
  • Polycystic Disease in Adults
  • Sickle Cell Anaemia
  • Tay Sachs
  • Thalassemias

• Basic Information
  • • The disease occurs only if both pair of chromosomes are altered.
    • Heterozygote (healthy) carriers of a recessive disease are known as carriers and show no phenotypic evidence of the disease.
    • If both parents are heterozygote carriers, the offspring have a 25% probability of inheriting the disease, a 50% probability of becoming a disease carrier, and a 25% probability of being unaffected.  These are numbers worth knowing.
      
    • Enzyme deficiencies are often inherited in an autosomal recessive fashion.
    • The symptoms of autosomal recessive disorder are usually more severe than those of autosomal dominant disorders and onset of disease is often in childhood .
    • Increased risk in families with consanguinity

1. Downs Syndrome – trisomy on chromosome 21 – presence of all or part of a third copy of chromosome 21.
2. Polysomy – Klinefelters  (47XXY)  – extra X sex chromosome in males, XYY syndrome, Triple X syndrome (XXX)
3. Monosomy – Turners  (45X0 or 45X)  – missing an X in the sex chromosome pair in females.

• Basic Information
  • Numerical chromosomal aberrations: an abnormal number of copies of a single chromosome – extra or missing chromosome
  • Remember, normal humans have a pair of 23 chromosomes i.e. 46 chromosomes in total in every somatic cell.

• Leber hereditary optic neuropathy
• Mitochondrial Myopathies (e.g. MELAS syndrome)

Basic information

• Mitochondrial DNA is maternally inherited.
• Diseases caused by mutations in mitochondrial DNA are only passed down from mother to offspring.
• Any offspring of an affected mother may show signs of the disease.
• Heteroplasmy:  Each mitochondrion has multiple copies of DNA (mtDNA), and each cell has many mitochondria. All of the DNA within the mitochondria is the same. If a mutation occurs, it usually is observed only in some of the mtDNA copies. This heterogeneity among mutated and normal mtDNA is known as heteroplasmy.
• Disease severity often correlates with the proportion of mutated mtDNA copies.

Hopefully, mitochondrial abnormalities will not come up in the CSA exam.  It’s confusing enough with the other genetic abnormalities.  We are training to be GPs, not geneticists!

• Androgenic Alopecia
• Alzheimer’s disease
• Atopy
• Diabetes Mellitus (Types 1 & 2)
• Hypertension
• Schizophrenia

Basic Information

• Polygenic diseases are the result of an interaction of two or more genes.
• Polygenic diseases do not follow Mendelian laws of inheritance.
• It’s not just genetic diseases that are a result of an interaction of two or more genes.    Other (normal) things are too like eye colour, skin colour, height and weight.

• These are disorders that are influenced by various factors (genetics, external influences like lifestyle and environment)
• Most diseases are caused by multiple factors
• Many people think most cancers are inherited disorders – they are not.
• Most cancers are a result of various factors – where lifestyle and environment plays a major part on the genetics eg smoking.