Article Text

Tuberous sclerosis complex: from basic science to clinical phenotypes
  1. F O’Callaghan

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Edited by Paolo Curatolo. Cambridge: Cambridge University Press, 2003. £55.00 (hardback), pp 301. ISBN 1 898 68339 5

Tuberous sclerosis has always had the capacity to confuse clinicians. Friedrich von Recklinghausen confused it with neurofibromatosis, when on 25 March 1862 he presented a case to the Obstetrical Society of Berlin. The case he described was of a young infant who had died soon after childbirth and who was discovered on postmortem examination to have multiple cardiac myomata in the ventricular walls and a “great number of scleroses” in the brain. It was a French physician, Desire Magloire Bourneville, a pupil of Charcot, who has won the plaudits for correctly appreciating that tuberous sclerosis was a separate disease. In 1879 he described the case of a 15 year old girl who died at the Salpetriere in Paris. She had suffered from epilepsy and severe learning difficulties for most of her life and was afflicted with a disfiguring vesicular-papular eruption on her face. An autopsy revealed that she had many hard sclerotic lesions in the cerebral cortex and white nodular lesions protruding into the lateral ventricles. Bourneville coined the term “tuberous sclerosis of the cerebral convolutions” for this unique pathology. The term tuberous sclerosis has stuck, although the French still patriotically talk of Bourneville’s disease.

Part of the reason that tuberous sclerosis has confused us, and still does, is that there has been a relative lack of population based research of the disease. In 1908 Vogt proposed a triad of clinical features that he felt characterised the disease, namely seizures, mental handicap, and “adenoma sebaceum”. No doubt the description accurately reflected his anecdotal clinical experience. It is still quoted in medical textbooks to this day. However, it grossly oversimplifies the disease. Epidemiological studies of the disease have revealed that more than half of those with tuberous sclerosis complex (TSC) will have a normal intellect and that complications related to the disease may occur in any organ of the body. The plea for more epidemiological research is not just an academic point. Patients may, and probably do, suffer if clinical decisions about their medical care are based on the results of hospital case series that are distorted by selection biases.

Professor Curatolo’s book goes a long way to demystifying this complex disease. Occasionally the authors fall into the trap of uncritically quoting many of the aforementioned misleading case series. However, this is more than compensated for by some excellent chapters within the book on the neurological and neuropsychiatric complications of the disease. The piece on the cognitive and intellectual impairments of the disease is the most balanced and comprehensive summary of the subject to date. Bolton clearly points out that the majority of TSC individuals fall within the normal range of IQ, but also suggests that many of those with high intelligence may also have specific neuropsychological impairments. He also explores the question of what causes the intellectual impairments in TSC in some detail and concludes that it is likely to be related to not just the extent of the structural brain abnormality but also the age of onset and type of seizure disorder as well as the nature of the underlying genetic mutation.

Curatolo and Seri’s chapter on seizures is also strong. Particularly interesting is the discussion of how epileptogenesis in TSC may be related to an impairment of GABA mediated neuro-inhibition. It is startling how well vigabatrin, a specific inhibitor of gamma amino butyric acid aminotransferase, is supposed to work in the treatment of infantile spasms in tuberous sclerosis. In Hancock and Osborne’s Cochrane Review of the treatment of infantile spasms, they found that there was a 95% response rate in those individuals with TSC who were treated with vigabatrin. The acid test of this therapy, of course, will be to see whether the apparent remarkable success rate in stopping spasms is matched by an improved intellectual outcome in these patients later in life.

The genetics of TSC are fascinating, and Kwiatkowski and colleagues carefully and clearly take the reader through the complexities of the subject. The disease is caused by alterations in two genes, TSC1 and TSC2, on chromosomes 9 and 16 respectively. Both are tumour suppressor genes and mutations in either can be responsible for all the complications seen in the disease. The gene products of the two genes, hamartin and tuberin, appear to act together in the regulation of cell growth by inhibiting a substance known as mTOR (target of rapamycin). In those individuals with the disease this inhibition is thought to be reduced and therefore there is the formation of the hamartomas that are characteristic of the disease. It is exciting that rapamycin, a clinically available compound, also selectively inhibits mTOR and therefore there is now the possibility that rapamycin may provide some benefit in reducing the clinical manifestations of TSC. Fittingly, Professor Curatolo’s book finishes with the intriguing suggestion that at last we may be on the threshold of being able to do something to ameliorate this complex and potentially devastating disease.