X-linked mental retardation and alpha thalassaemia

This is the rare association of HbH disease and X linked mental retardation.

ATR-X is found in North European populations.

ATR-X is an example of a chromatin-remodeling disorder (see notes)

• there is no evidence for the 16p13.3 deletions which typically disrupt the alpha globin gene in HbH disease
• the disease locus of ATR-X has been localized to the region Xql3.3 off the X chromosome
  • the ATRX gene encodes X-linked helicase-2 (XH2)
    • the ATRX complex is a down-regulator of the alpha-globin locus, resulting in thalassaemia. The presence of alpha thalassaemia, in conjunction with mental retardation, is indicative of ATR-X
  • the genetic mutation is carried by the mother, as with other Xlinked syndromes - there is an X-inactivation exhibited by carriers

There is a remarkably uniform phenotype, comprising:

• severe mental retardation
• characteristic facial dysmorphism
• genital abnormalities
• mild form of HbH disease

There is no treatment for this syndrome.

Notes:

• 'chromatin-remodeling' disorders, are unique in medicine because they arise from a general deregulation of DNA transcription. Without proper regulation of transcription, cells produce proteins in a thoroughly disordered way, resulting in dysfunctional macromolecular processes (2)

Reference:

1. R.J. Gibbons et al. "A newly defined X linked mental retardation syndrome associated with alpha thalassaemia". J. Med. Genet. 1991; 28: 729-33
2. Ausio J et al. Syndromes of Chromatin remodeling. Clinical Genetics 2003; 64(2):83-95