X-linked and mitochondrial disease

Characteristics of sex-linked inheritance

Refers to patterns of inheritance of genes located on the sex chromosomes

  • X-linked recessive
  • X-linked dominant
  • Y-linked
  • X-linked recessive (most common)

Characteristics of X-linked recessive inheritance

Determined by gene encoded on X chromosome

  • Mutant allele encodes a trait that is recessive compared to that from the normal allele
  • Therefore, 2 mutant alleles required for female to be affected
  • Need 1 mutant allele for males to be affected

Disorder usually only affects males, said to be hemizygous

Recognizing an X-linked recessive trait from a pedigree

  • More than one generation involved
  • Usually only males affected
  • No male to male transmission

Genetic risks for X-linked recessive disease

  • 25% from carrier mother
  • 25% for daughters from carrier fathers


  • Red-green colour blindness, by far most common (800/10000 males)
  • Fragile X syndrome (5/10000 males)
  • Non-specific X-linked mental retardation (5/10000 males)

Duchenne muscular dystrophy (DMD)

Muscle degenerative disorder

  • Presents in infancy: Delayed walking, waddling gait, Gower's sign
  • Calf pseudohypertrophy
  • Develop progressive weakness: wheelchair by 10 years
  • May have cardiac muscle involvement
  • May be intellectual impairment

Death in late teens - respiratory muscle weakness


  • Serum muscle enzymes: Very high levels of creatine kinase (dystrophy of muscle)
  • Muscle biopsy: Absence of staining with antibodies to dystrophin
  • Molecular genetic analysis: Identification of deletions/mutations in dystrophin (best way of confirming)

Molecular genetic analysis

This is done via the polymerase chain reaction

Types of mutation in DMD

  • Deletions
  • Point mutations
  • Premature stop codons
  • Altered splice site mutations (lose splicing of exons or add exons that shouldn't be there)
  • Promoter mutations

Mutations that alter the reading frame in 2/3 cases. The size of the deletion doesn't correlate with severity

Mutation in DMD

Doesn't alter reading frame of downstream proteins, much milder disease, normal life expectancy

Becker muscular dystrophy

  • Milder
  • Less severe muscular weakness
  • Mean onset 11 years
  • Ambulant until adult life
  • Life expectancy only marginally reduced

Dystrophin analysis

  • In-frame deletions
  • Protein analysis downstream of deletion- normal

Genetic counselling in X-linked recessive diseases

This is very important as all carrier females have 25% risk of having affected sons

How to tell if a female relative is a carrier

  • Direct gene testing (best way) need to know mutation
  • Serum creatine kinase estimation
  • Muscle biopsy (dystrophin antibodies)

The curve for serum ck levels is shifted to the right, higher on average, but doesn't have an effect on carrier

Risk analysis

  • Chance that she is a carrier = 0.5
  • Chance that she will have an affected child = 0.5 x 0.5 (inherit defective allele) = 0.25

Molecular analysis

  • Molecular genetic testing of affected males is the first step
  • New mutations very common in DMD (1/3)
  • This is done through genotyping with genetic marker that maps within the dystrophin gene

Why do females show X-linked recessive traits

1. Skewed X-inactivation: More likely to inactivate one X over the other, mild features of disease

2. Turner's syndrome: XO (one X chromosome, show disease)

3. Homozygous for a recessive trait: E.g. colour blindness (XaXa)

4. Chromosomal rearrangements involving the X chromosome and an autosome (autosomal translocation): The X chromosome involved in the translocation survives preferentially, thus the "messed up" X chromosome is not inactivated.


  • X-inactivation is clonal and random
  • This is done in order to balance the dosage of gene product (dosage compensation)


  • X-inactivation spreads from an X inactivation centre on Xq
  • The XIST gene, expressed from the inactive X is important in maintaining the silenced state of the rest of the X chromosome
Inactivation occurs randomly in each individual cell, it occurs in the female embryo with approximately 50% of each cell

Skewed X-inactivation

In order to maintain the autosomal bit (otherwise cause cell death), the other X chromosome is favoured to be deactivated

X-linked dominant disease

Pedigree similar to autosomal dominant

  • But excess of affected females
  • No male to male transmission
  • Uncommon, e.g. Vitamin D resistant rickets

Y-linked (holandric) inheritance

Only males affected

  • Affected males pass trait to all sons, none of daughters
  • Examples include H-Y histocomptability antigen, hairy ears

Sex influence

  • When autosomal traits are expressed more frequently in one sex than another (e.g. gout, presenile baldness in males)
  • This is due to hormones rather than autosomal chromosomes

Sex limitation

  • Appearance of certain features in individuals of only one sex
  • E.g. Virilization of female infants with congenital adrenal hyperplasia, autosomal recessive disorder

Mitochondrial inheritance

  • Mitochondria has its own DNA, 37 genes for 13 proteins (for respiratory chain)
  • Majority of proteins in mitochondrial proteins made in nucleus and imported into mitochondria (nucleus dependent)

Key features of inheritance

  • Exclusively maternal inheritance
  • This is because sperm mitochondria expelled from egg

Mitochondrial DNA sequences can be used to follow DNA lineage as there is no cross over (although mutations still occur)

Mitochondrial DNA and disease

Mutation in mitochondrial DNA means that everybody is affected


  • Heteroplasmy: If a mutation arises, it will create a mixed population of mitochondria within cell. Lots of mitochondria needed to have effect.
  • Replicative segregation: When cells divide, mitochondria partitioned at random

Effects may vary, thus genetic counselling has to be varied. Difficult to get genetic diagnosis, need to sample tissue where gene has effect


  • Muscle weakness
  • Epilepsy
  • Deafness
  • Optic atrophy
  • Diabetes
  • Cardiomyopathy
  • Aplastic anaemia

Key points

  • Not all inherited disorders of mitochondria result from mutations in mitochondrial DNA (some come from the nucleus)
  • Phenotype of inherited mitochondria disease variable, often multisystem
  • Characteristic inheritance patterns
  • Severity of disease varies with heteroplasmy and threshold effects