X-LINKED RECESSIVE

X linked inheritance can be either recessive or dominant. In the recessive type, in the case of the male, if the only available X carries the mutant gene, the male is affected. Fig. 31. This is a hemizygous state. If the gene on the X is normal, then the male is normal. There are no carrier states in the male. In the female however, there are normal homozygous states, the affected homozygous states and the heterozygous carrier states.

CRITERIA

1. Hemizygous affected males do not transmit the trait to children of either sex, but all daughters are heterozygous carriers.
2. Female heterozygous carriers will transmit the trait to 50% of the sons who will manifest the disease and 50% of daughters making them carriers.
3. There are more males than females. Fig. 32.
4. Affected females are produced from matings between affected males and heterozygous carrier females.
5. Every affected male is born of a heterozygous female with the exception of a new mutation.
6. Female heterozygotes may exhibit a wide spectrum of clinical features due to random X inactivation.

SPECIAL FEATURES

1. In a sporadic case, it may be a new mutation or the mother may be a heterozygous carrier.
2. Heterogeneity may be seen where the clinical features are similar but inherited through different mechanisms. For example, the autosomal recessive albinism affects the skin, hair and eyes, while the X - linked type is purely ocular and this can be overlooked in a blond child.
3. An affected female may be any of the following :

1. An affected homozygote
2. A heterozygote, in whom due to lyonization the proportion of mutated active X chromosomes is higher.
3. The patient is a 45,X Turner syndrome
4. The patient is a 46,XY Androgen Insensitivity syndrome (Testicular Feminization syndrome)
5. The patient had an affected father and a new mutation on one X in a normal mother
6. The patient has a heterozygous carrier mother and a normal father with a new mutation on his only X.
   
   In Turner syndrome with a normal X and the other an isochromosome of the long arm of X, the abnormal isochromosome is selectively inactivated, so that if the normal X had just one recessive gene the female would be affected.
   
   The opposite is seen in an X-autosome translocated chromosome. Here, if the recessive gene was on the translocated chromosome, the normal chromosome is always inactivated allowing the abnormal translocated chromosome carrying the recessive gene to remain active, producing an affected female.
   

1. X-linked lethal conditions are those where affected males die before birth disturbing the sex ratio in favour of more females, who will survive with one mutant gene as carriers.

CLINICAL EXAMPLES

1. Duchenne muscular dystrophy is due to a mutation of a gene located on the short arm of the X chromosome (Xp21). The gene product is a muscle protein dystrophin which acts as a fibre protector. In the absence of dystrophin, in the first year of life the disease begins with progressive muscle weakness. Later there is muscle wasting, hypertrophy of calf muscles and finally death in the teens or early twenties following cardiac or respiratory failure.
2. Fragile X syndrome is the commonest inherited mental retardation, which is more common in males, who when affected have mild to moderate educational subnormality, speech delay, possible autistic features, large ears, prominent chin and megalotestis (macroorchidism). Affected females are usually milder. Blood or tissue samples of the affected when cultured in media containing low folate, produce fragile sites at the tips of the long arms of the X chromosome. This condition may even be classified as a chromosome aberration.
3. G 6PD deficiency.
4. Red-green colour blindness.
5. Ocular albinism.
6. Becker muscular dystrophy.
7. Classical haemophilia A.