Dr Alison M Kerr:        handout for lectures 2004

Perhaps the most important message for people with ken syndrome and their families is that in spite of their severe disabilities in thinking and in movement it is still possible for these people to live long in good health and to enjoy life.

Although Andreas Rett described the condition in 1966, by 1982 it was still little known or understood. A paper by Hagberg at al alerted the English-speaking world and after 1982 national surveys in Britain, Sweden, Japan and the USA led gradually to a better understanding of the natural history of the disease. Examination of the brain shows selective failure in the connections between neurones. There are severe abnormalities in the densities of receptors for serotonin and glutamate, important neurotransmitters (chemical messengers). In 1999 it was discovered that the syndrome results when a gene on the X chromosome, MECP2, develops a fault The active protein produced by MECP2 - designated MeCP2 - influences the activities of other genes some of which have now been identified. These include UBE3 (involved in Prader Willi and Angelman syndromes) and Brain derived neurotrophic factor (BDNF) which is involved in brain development and breathing control.

The mutation usually occurs in sperm (thus passing to female offspring), less often in ova and quite rarely in the already formed embryo. Males are therefore seldom affected but having only one X chromosome are likely to be very severely affected. Females are protected by having two X chromosomes per cell. Since only one X is used in each cell the disease severity depends on the extent to which the mutated X is used. Thus the severity in different people ranges from very mild to very severe, although most are severely affected. In about 90°% of people with clinically undoubted (classical) Rett syndrome MECP2 mutations are found. About half of those with some but not all the signs of Rett (‘non-classic’, ‘atypical’ or ‘variant’) also prove to have MECP2 mutations and testing should be offered in any such case. Some people with ‘non-classic’ Rett have mutations in other genes affecting some of the same processes in the brain - such as the recently reported gene STK9. It has been reported that particular mutations on MECP2 may lead to non-ken phenotypes.

Babies with Rett disorder generally look normal at birth and make some developmental progress however the normal spontaneous movements are disrupted and posture is disturbed from birth. A regressive event, usually at 1-2 years, particularly affects speech and hand use, which diminish. Stereotyped hand movements become evident, tremor is present and muscle tone (tension) is disturbed — often reduced initially and then increased — dystonic and hypertonic. Thereafter the disorder is essentially static although the consequences are severe and manifest serially with age. About half learn to walk, some quite late in life. Movement at the joints readily becomes restricted, perhaps due to the abnormal muscle tone. To avoid contractures, including scoliosis (curvature of the spine) it is important to encourage normal movement at all the joints. Regular physiotherapy is most helpful but where that is not available simple exercises, learned from the physiotherapist and regularly carried out will be of benefit. If scoliosis progresses beyond 40 degrees, specialist surgery is generally recommended in the UK. Feeding may become difficult due to problems with lip closure, chewing, swallowing, involuntary movements and erratic breathing. In a minority of people alternative feeding is necessary and in the UK a fine tube introduced through the skin into the stomach (PEG) has been found satisfactory. That requires long-term support from the operating team. Constipation and reflux of acid from the stomach into the oesophagus are common and usually respond to simple remedies. Brain stem control of cardio-respiratory rhythms is inadequate, leading to very irregular breathing, rapid fluctuations in heart rate and blood pressure and sudden interruptions of consciousness (vacant spells). Epileptic seizures occur in over 50 but vacant spells are much more frequent and are commonly mistaken for and incorrectly treated as epileptic fits. When there is doubt, simultaneous electroencephalography and autonomic (brain stem) monitoring should be ca out Brain stem attacks are probably responsible for at least one fifth of the deaths recorded in Rett. In Britain death has occurred in just over 1% of cases each year, more than half occurring in the most severe cases during early adult life. However many people, including some very severe, remain healthy and live beyond 50 years

With advances in understanding of the genetic and biochemical basis for Rett problems there is hope that effective treatment will be found. However we discourage the routine use of any medication before it is thoroughly tested on animals and monitored in clinical trials. Presently recommended are anticonvulsants if necessary, specific medication for the breathing dysrhythrmia — only after autonomic assessment and symptomatic treatment for problems such as constipation and gastro-oesophageal reflux.

In spite of their difficulties even severely affected people with Rett retain and develop personality. Given regular activity, — nutrition and attention to their medical needs they can remain in good health. A great strength is their enjoyment of other people. They remember people and places, develop real relationships and can make and enjoy their own choices. After the infant regression period has p usually by 5 years of age, they make progress in learning. Communication improves and so may hand use and mobility. Vision and hearing remain good. It is important to arrange for periodic fill assessment of the potential for communication and mobility and to expect and encourage development. Only a few people with Rett have useful speech but all love to communicate and individual music therapy is particularly well suited to encourage interaction. Physical activity is essential for health and is enjoyed. Well-supported activities - walking, horse riding and in water are usually enjoyed and beneficial. It has to be remembered that much of the normal development of the brain at all ages depends on active use of the existing pathways which link neurones and neglect of skills leads to their joss. It is therefore very important and truly therapeutic to encourage the use and development of skills in people with Rett.

Kerr AM. Outcome in Ret! Syndrome. (2002) In:- Outcomes in neuro-developmental and genetic disorders. Ed Goodyear I & Howlin P. Cambridge University Press, Cambridge. P241-271

Kerr AM, Witt Engerstrom I.(editors)(2001) Rett Disorder and the Developing Brain. Multi-author text book. Oxford University Press, Oxford ISBN 0192630830

Julu, P.0.0. Kerr, AM,, Apartopoulos, F, Al-rawas S, Witt Engerstrom, I., Engerstrom L, Jamal GA and Hansen, S.(2001) Characterisation of breathing and associated autonomic dysfunction in the Rett Disorder. Archives of Disease in Childhood. SS 29-37.

Burford B Kerr AM and McLeod H (2003) Nurse recognition of early Deviation in Development in Home videos of infants with Rett Syndrome. Journal of Intellectual Disability Research 47:8;588-596

Kerr AM, Cass H, Weekes L, Slonims V, Bridgeman G and Wisbech A (2003) Clinical checklist for patients with Rett Disorder and Individuals with Rett disorder and the role of the physician Primary Psychiatry:10: Physician Patient resource series p32-33 & 59-62 

Kerr A M, Webb P, Prescott R and Milne Y (2003) Results of Surgery for scloliosis on Rett Syndrome.  Journal of Child Neurology:18:10;703-708.