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Objectives The indications for surgery and outcomes of patients who underwent surgical removal of subependymal giant cell astrocytomas (SEGAs) in our institution between 2000 and 2011 were reviewed. Methods We reviewed the clinical details of 16 patients with a diagnosis of Tuberous Sclerosis Complex (TSC) who underwent surgery for SEGA in Bristol since 2000. We collected information on age, sex, epilepsy history and cognitive status. We reviewed the indications for surgery, age at surgery, surgical approach, and the size and location of the lesions. We analysed mortality, completeness of tumour resection, intraoperative blood transfusion, shunt placements, and surgical complications. Results 13 patients had surgery due to hydrocephalus. Increasing size of SEGA without hydrocephalus was an indication for surgery in two patients, and in one patient, the SEGA was removed because of its size and location at initial scan. 13 patients had complete tumour resection. One patient had tumour recurrence. Hydrocephalus failed to resolve or reoccurred in four patients post operatively necessitating shunt insertion. The surgical approach was transcortical in 14 patients and transcallosal in two. There was zero mortality in this series. There were no reports of cognitive decline or worsening epilepsy following surgery. Conclusion Surgery is a safe and effective treatment for SEGA. It is the authors' view that surgery remains the most appropriate treatment strategy for SEGAs that are amenable to surgery. More work needs to be undertaken to assess prospectively the neurocognitive impact of surgery, and the relative advantages of different surgical approaches.

Purpose: To examine the underlying etiology of infantile spasms from the United Kingdom Infantile Spasms Study (UKISS), using the pediatric adaptation of ICD 10. Methods:?Infants were enrolled in a randomized controlled trial or a parallel epidemiologic study. Etiological information included history, examination, and investigations. The infants were classified as proven etiology, if a neurologic disease was identified; as no identified etiology, if no neurologic disease was identified; and as not fully investigated, if a major piece of information was missing. Proven etiology was subclassified using the pediatric adaptation of ICD 10. The results were then examined to identify further methods of classification. Results: Of 207 infants, 127 (61%) had proven etiology, 68 (33%) had no identified etiology, and 12 (6%) were not fully investigated. Etiologies were prenatal in 63, perinatal in 38, postnatal in 8, and 18 other. The most common etiologies were: hypoxic–ischemic encephalopathy (HIE) 21 (10%), chromosomal 16 (8%), malformations 16 (8%), stroke 16 (8%), tuberous sclerosis complex (TSC) 15 (7%), and periventricular leukomalacia or hemorrhage 11 (5%). The remaining 32 etiologies were all individually uncommon. Response to treatment is given for individual etiologies. Discussion:?Our method of classification allows the reporting of results by individual diseases, disease groups, or categories and is structured and clear. It avoids the use of poorly defined terms such as symptomatic and cryptogenic. It can adapt to new neurologic diseases, such as gene defects, and can be used for comparison of different groups of infants, thereby aiding meta-analysis.

Objectives: In a population based study of tuberous sclerosis (TSC), we sought firstly to identify the number of patients who have presented with symptomatic giant cell astrocytomas (GCAs) and secondly, within a subset of this population, to identify the number who would be diagnosed with GCAs on predetermined radiological criteria. Methods: Individuals with TSC in Wessex (a geographical region of England) were identified and their medical history determined. A subset of individuals were invited to have a cranial MRI if they did not have a history of a symptomatic GCA and if they were likely to tolerate having cranial imaging without a general anaesthetic. Scans were performed according to a standard protocol on a single scanner and were reported blindly by a neuroradiologist. Results: 179 individuals were identified with TSC. Ten of the 179 individuals had a history of treatment for a symptomatic GCA. 41 individuals had a cranial MRI. Thirty-nine had subependymal nodules of whom 24 (59%) had at least one (maximum 11) which enhanced with gadolinium. In seven individuals (17%) the lesion was greater than 1cm and all of these lesions enhanced. Conclusions: In this study, the proportion of those with TSC who had a history of symptomatic GCA was 5.6%. In the subset without such a history, who underwent imaging, the number diagnosed as having a GCA on radiological criteria was much higher (59% enhanced and 17% were greater than 1cm in size). Screening for giant cell astrocytomas (performing scans on asymptomatic individuals with TSC) would, therefore, identify large numbers of patients who had not presented with symptoms. This finding leads us to recommend that screening should not be undertaken.

To determine normal melatonin excretion patterns in healthy children without sleep disorder and to compare these with those of patients with tuberous sclerosis complex and sleep disorder responsive to exogenous melatonin, we measured 6-sulfatoxymelatonin excretion in 21 healthy children and in 7 patients with tuberous sclerosis complex and sleep disorder responsive to melatonin (a 5 mg oral dose increasing total sleep time). Total excretion, cosinor percentage, and acrophase time of 6-sulfatoxymelatonin excretion were estimated. In normal children, total 6-sulfatoxymelatonin excretion was range 11.1 to 40.2 μg (mean 19.0 μg, SD 7.4 μg); cosinor percentage rhythm range was 52.9% to 100% (mean 87%, median 94%); and acrophase time range was 23 hours, 54 minutes to 10 hours, 42 minutes (mean 5 hours, 54 minutes; median 4 hours, 12 minutes). Fifth and 95th percentiles were 11.1 to 29.0 μg, 57.8% to 99.9%, and 2 hours, 1 minute to 10 hours, 4 minutes. In tuberous sclerosis, normal patterns of melatonin excretion were seen in responders. Circadian patterns of melatonin excretion were similar in children and adults. We propose that exogenous melatonin can act by a simple sedative action. ( J Child Neurol 2005;20:21—25).

Objectives: To report the frequency of renal symptoms and complications of patients with tuberous sclerosis complex (TSC), to describe the ultrasonographic appearance of the kidneys in a population-based sample, and to investigate the relationship between a history of renal haemorrhage and renal lesions identified by ultrasonography. Patients and Methods: As part of an epidemiological study, 179 patients with TSC were identified as living in the Wessex Region in the South of England. Patients were interviewed and examined in their homes, to elicit the presence of renal symptoms or a history of renal complications. Renal ultrasonography was used in consenting patients in their homes. Results: There was a history of renal complications in 16 (9%) patients; 149 consented to interview and examination, and 19 gave a history of renal symptoms in the previous year; 124 had renal ultrasonography; 86 (69%) had renal angiomyolipomas and 37 (30%) had renal cysts. Large lesions (>3 cm in diameter) were strongly associated with a history of symptomatic bleeding, although significant haemorrhage occurred in a 6-year-old child with small angiomyolipomas. Conclusions: The formation of angiomyolipoma in TSC is common. Polycystic kidney disease, renal carcinoma and renal failure, although rare, occur in TSC. Most patients with angiomyolipomas have neither complications nor symptoms. There was no appreciable difference between the sexes in the risk of developing these lesions. Although less commonly seen in the very young, there is no identifiable relationship after adolescence between age and the risk of having a renal angiomyolipoma. Bleeding tends to occur from large lesions (>3 cm) but most such patients have remained asymptomatic to date.

About 60 children are born each year in the UK with tuberous sclerosis. Half will present with infantile spasms while one-quarter will have neither epilepsy nor learning difficulties. Management of epilepsy in the pre-school child is difficult but necessary as better control is associated with an improved outcome. Regular cranial scans are not necessary but investigating symptoms of raised intracranial pressure is urgent. Behavioural problems are common and include autism, hyperactivity, sleep disorder and deliberate self-harm. Renal disease, usually due to angiomyolipomas (AML), is common but symptoms of bleeding are not. If frank haematuria occurs, preserve the kidney if at all possible. DNA analysis of the two genes is difficult and is not suitable for exclusion of the disease in a sporadic case. The protein products control cell growth and this pathway may soon prove amenable to control with medications.

Background. Intellectual impairments are a recognized feature of tuberous sclerosis complex (TSC), but the frequency and degree of intellectual impairments has not been systematically studied in large epidemiological samples using standardized measures. As such, the form of the IQ distribution (uni- or bi-modal) has not been established and the relationship between IQ and other features (e.g. epilepsy history) is poorly delineated. To address these shortcomings, we assessed the intellectual abilities of a large epidemiological sample of individuals with TSC, drawn from the ‘Wessex’ area of SW England and compared them with the abilities of their unaffected siblings.Method. Standardized tests were used to estimate the abilities of 108 (56 males, 52 females, median age=25, range=4–75) individuals with TSC and 29 unaffected siblings (14 males, 15 females, median age=18, range=6–55). Seizure history was obtained from informants and medical records.Results. Estimated IQ was bi-modally distributed: 55·5% had an IQ in the normal range; 14% had mild to severe impairments; and 30·5% had profound disability (IQConclusions. Intellectual abilities were bi-modally distributed in a representative sample of individuals with TSC. The likelihood of impairment was associated with a history of seizures, particularly infantile spasms. The genetic and brain basis of these findings requires further investigation.

Tuberous sclerosis (TSC) is an inherited disorder best known for its association with severe learning difficulties, epilepsy, behavioural problems, skin and renal pathology. Lymphangioleiomyomatosis (LAM), characterized by alveolar smooth muscle proliferation and cystic destruction of parenchyma, occurs as an infrequent symptomatic pulmonary complication in TSC and as a very rare sporadic disease in those without signs of TSC. Considered a generalized and progressive cystic lung disease that is difficult to treat with a poor prognosis, it has been reported almost exclusively in women, most commonly presenting with dyspnoea and pneumothorax in those of childbearing age. We investigated the clinical features and prognosis of LAM in patients with TSC including the effects of treatment, stratified by the method of diagnosis of LAM (i.e. histological or radiological). We found histological proof of diagnosis in 10 of 21 patients with TSC and symptomatic lung disease, onset in childhood in four, three males with LAM, individuals with apparently focal disease, great variation in clinical course and no clear treatment benefit. In those with TSC, symptomatic LAM is infrequent but causes a significant morbidity and mortality. It was not possible to detect predisposing factors, other than being female. Males with apparent LAM should be rigorously investigated.

The purpose of this report is to review the efficacy and safety of vigabatrin in the treatment of infantile spasms in infants suffering from tuberous sclerosis complex. We reviewed all studies published in the English-language literature investigating the use of vigabatrin in the treatment of infantile spasms. Ten studies gave results for the efficacy of vigabatrin in infantile spasms for infants both with and without underlying diagnoses of tuberous sclerosis. Of the 313 patients without tuberous sclerosis complex, 170 (54%) had complete cessation of their infantile spasms; of the 77 patients with tuberous sclerosis complex, 73 (95%) had complete cessation of their seizures. We conclude that vigabatrin should be considered as first-line monotherapy for the treatment of infantile spasms in infants with either a confirmed diagnosis of tuberous sclerosis or those at high risk, ie, those with a first-degree relative with tuberous sclerosis complex. Paradoxically, in those without tuberous sclerosis complex, vigabatrin might be less efficacious than suggested by studies including patients with tuberous sclerosis complex. (J Child Neurol 1999;14:71-74).

The entire coding region of the TSC1 gene has been screened for mutations in 79 unrelated patients with tuberous sclerosis. Causative mutations have been found in 27 of these patients and five other variations in the gene have been identified. 26 of the mutations are predicted to cause premature truncation of the protein product of the gene and one mutation is in a splice site. The mutation screen has revealed that TSC1 mutations are rarer in sporadic tuberous sclerosis patients than in familial cases. We have also found that the only previously described case of non-penetrance can no longer be described as such, and that a single ungual fibroma is not necessarily diagnostic of tuberous sclerosis, important findings for the genetic counselling of tuberous sclerosis patients.

This report highlights the association between tuberous sclerosis and Wolff-Parkinson-White syndrome. Ten patients with concurrent diagnoses of Wolff-Parkinson-White syndrome and tuberous sclerosis were identified. Wolff-Parkinson-White syndrome presented early in life, nine cases being diagnosed in the first year. Eight of the 10 cases were male. In eight cases, the syndrome was associated with supraventricular tachycardias, and in nine with cardiac rhabdomyomata. One child died from cardiac failure secondary to obstruction of the left ventricular outflow tract by a rhabdomyoma. Five of nine survivors showed resolution of Wolff-Parkinson-White syndrome on follow up. The accessory pathway was localised in nine patients from surface electrocardiograms: six children had left sided pathways and three had right sided pathways.

We report the cross-sectional age-related prevalence of cutaneous features of the tuberous sclerosis complex in a defined population. Of 131 affected individuals, 126 (96%) exhibited skin signs. Although there is considerable variation in the age of expression of all the skin lesions, there is a trend towards the earlier expression of hypomelanic macules and forehead fibrous plaques compared with facial angiofibromas and ungual fibromas. Shagreen patches are usually present by puberty. Ungual fibromas appeared for the first time as late as the fifth decade and were the only clinical feature in three individuals. Gum fibromas were present in 36%. Ten individuals (8%) presented because of the skin manifestations and 21% received treatment for symptomatic skin lesions. Two individuals had large hamartomas at unusual sites (occiput and forearm).

SUMMARY 32 families informative for the segregation of Tuberous sclerosis (TSC) have been examined for genetic markers on chromosomes 9, 11, 12 and 16. In one large family there was clear evidence of linkage to markers on chromosome 16p13.3 (lodscore with D16S291 of 4·7 at θ= 0) but other families were too small to give individually convincing lodscores. Combined results for all families gave positive results with ABO/DBH on chromosome 9 (max lod 2·63) and with D16S291 on chromosome 16 (max lod 3·98) at values of theta of 0·2 in each case. Further analysis showed strong evidence for heterogeneity with approximately half the families linked to a locus TSC1 on chromosome 9 between ASS and D9S298 and half to TSC2 on chromosome 16 close to D16S291. There was no definite support for a third locus although in many families this could not be excluded. In three families the segregation pattern of TSC remains unexplained. In two of these the family apparently segregates for TSC1 but in each case a single affected individual appeared to exclude the whole of the candidate region. Preliminary analysis of clinical features did not reveal any definite differences in incidence of mental handicap between individuals in different linkage groups or with different sex of the parent of origin. The frequencies of periungual fibromas and facial angiofibromas were also similar in both linkage groups. The difficulties of detecting linkage in small families where there is locus heterogeneity are discussed. The program ZZ was found to be helpful in this respect.

To examine the underlying etiology of infantile spasms from the United Kingdom Infantile Spasms Study (UKISS), using the pediatric adaptation of ICD 10.Infants were enrolled in a randomized controlled trial or a parallel epidemiologic study. Etiological information included history, examination, and investigations. The infants were classified as proven etiology, if a neurologic disease was identified; as no identified etiology, if no neurologic disease was identified; and as not fully investigated, if a major piece of information was missing. Proven etiology was subclassified using the pediatric adaptation of ICD 10. The results were then examined to identify further methods of classification.Of 207 infants, 127 (61%) had proven etiology, 68 (33%) had no identified etiology, and 12 (6%) were not fully investigated. Etiologies were prenatal in 63, perinatal in 38, postnatal in 8, and 18 other. The most common etiologies were: hypoxic-ischemic encephalopathy (HIE) 21 (10%), chromosomal 16 (8%), malformations 16 (8%), stroke 16 (8%), tuberous sclerosis complex (TSC) 15 (7%), and periventricular leukomalacia or hemorrhage 11 (5%). The remaining 32 etiologies were all individually uncommon. Response to treatment is given for individual etiologies.Our method of classification allows the reporting of results by individual diseases, disease groups, or categories and is structured and clear. It avoids the use of poorly defined terms such as symptomatic and cryptogenic. It can adapt to new neurologic diseases, such as gene defects, and can be used for comparison of different groups of infants, thereby aiding meta-analysis.

Medical textbooks still define tuberous sclerosis (TSC) as a triad of clinical features, mental retardation, epilepsy and “adenoma sebaceum”, first described by Vogt in 1908.1 2 Not surprisingly therefore many clinicians still do not realise that half of TSC sufferers will have normal intellect, a quarter will not have epilepsy, and almost any organ in the body can be affected. Recent advances in molecular genetics and imaging have begun to unravel the complexity of the disease, explaining the mechanisms behind the clinical features and providing insights into how these patients should be managed. Gunther and Penrose described the autosomal dominant pattern of inheritance of TSC in 1935.3 We now know that there are two genes (and probably only two) causing the TSC clinical phenotype. TSC1 is found on the long arm of chromosome 9, and its protein product is called hamartin.4 The TSC2 gene's protein product is named tuberin and it is situated on the short arm of chromosome 16, only 48 base pairs of DNA from the gene for adult onset polycystic kidney disease (PKD1).5 This genetic heterogeneity in TSC raises the question of whether the clinical syndrome produced by the two different genes is the same. In some conditions, neurofibromatosis for example, genetic heterogeneity helps explain clinically distinct forms of the disease. However, all the complications of TSC have been seen in both TSC1 and TSC2 except for the contiguous gene deletion syndrome (see below). There may, however, be subtle differences in the phenotype produced by the two genes or by specific mutations. There is already some evidence from case series that mutations in TSC2 tend to produce more severe disease than TSC, but this needs to be confirmed in larger less biased studies.6 We may then see no significant differences in the …

Tuberous sclerosis (TSC) is a multisystem autosomal dominant hamartosis whose genetics is complicated by reduced penetrance and widely varying clinical expression. Results of linkage analyses have variously suggested two different locations for a TSC gene. A collaborative dataset has been assembled to clarify the issue of genetic heterogeneity. We have now analyzed the data from a combined sample of 111 families. Using Ott's HOMOG programs, we completed three tests of homogeneity: (1) for chromosome 9q, (2) for chromosome 11q, and (3) for the combined 9q and 11q data. For test 1 the chi-square (1 df) was 21.54 (p less than 0.001), for test 2 the chi-square (1 df) was 0.13 (p greater than 0.35), and for test 3 the chi-square (2 df) was 37.61 (p less than 0.0001). Additionally, we examined the combined data for evidence that a third, as yet unlinked locus exists. Results of this last test were suggestive but not significant. Clearly loci for TSC are present on both chromosomes 9q and 11q. The maximum likelihood estimate of the proportion of chromosome 9q-linked families is 0.38, for chromosome 11q-linked families is 0.47, and for the unlinked type 0.15. Alternative explanations for these latter families include chance sampling of recombinants, nongenetic phenocopies, or misclassification.

Author(s): Povey, S; Attwood, J; Janssen, LA; Burley, M; Smith, M; Flodman, P; Morton, NE; Edwards, JH; Sampson, JR; Yates, JR

In tuberous sclerosis, the protein products of the TSC1 and TSC2 genes, hamartin and tuberin, act together in regulating the P13 kinase-Akt-mTOR-S6 kinase cell growth pathway. This finding raises the possibility that drugs could substitute for the role of the hamartin-tuberin complex in this pathway and thereby ameliorate some aspects of the disease in affected individuals. One such drug, rapamycin, is currently beginning evaluation. Mutations are still only found in two thirds of affected individuals and a negative mutation screen should not be taken as evidence of absence of the disease. The need for detailed clinical examination and investigation remains paramount, especially in evaluating parents. Seizures in the first 5 years of life, but particularly in the first year, including infantile spasms, require urgent intervention. We do not advocate screening but we do suggest urgent evaluation for possible raised intracranial pressure secondary to giant cell astrocytomas and for bleeding from renal angiomyolipomas where preserving renal function is a priority.

BACKGROUND: Tuberous sclerosis (TS) is a multi- system disorder with complex genetics. The neurodevelopmental manifestations of TS are responsible for considerable morbidity. The prevalence of epilepsy and intellectual disabilities among individuals with TS have been well described. Ours is the first study that explores the prevalence and pattern of psychopathology in a population-based sample of adults with TS. METHODS: Sixty subjects were identified through a capture-recapture analysis of TS. Information was gathered as to seizure history, cognitive functioning (WISC-III) and psychopathology (SADS-L, SAPPA). Lifetime psychopathology was categorized according to Research Diagnostic Criteria. The overall pattern of mental illness (MI) was examined as well as how this varied with IQ and seizure history. RESULTS: Twenty-four (40.0%) subjects had a history of MI. The most common diagnosis was that of an affective disorder [18 (30.0%)], the majority of which were major depressive episodes. Alcoholism [4 (6.7%)] and anxiety disorders [3 (5.0%)] were the next most common diagnoses. Two (3.3%) subjects had had a tic disorder. Only one individual had a diagnosis of schizophrenia. MI was found in 75.0% of those with a history of epilepsy and 37.5% of those without epilepsy. MI was significantly more prevalent in those with a full-scale IQ above 70. CONCLUSIONS: A significant proportion of adult with TS experience MI. MI was significantly more [corrected] prevalent in subjects with a full-scale IQ above 70. Reasons for such a finding are explored, and related methodological considerations for future research outlined.

We report a randomized, double-blind, controlled, crossover trial investigating the response to oral melatonin using two dose regimens in patients with sleep disorders associated with tuberous sclerosis complex. Eight outpatients with tuberous sclerosis complex and sleep disorder received either 5 or 10 mg of melatonin. Sleep latency, total sleep time, number of awakenings, and seizure frequency were recorded in sleep and seizure diaries. No evidence of a dose effect between 5 and 10 mg was seen with respect to any outcome measure. (The 5 mg results are given first: sleep latency, 86 and 76 minutes; total sleep time, 8 hours, 57 minutes and 9 hours, 4 minutes; and sleep fragmentation, 0.8 and 1.0). This study might have missed a small beneficial effect of 10 mg melatonin. We propose that an initial trial of 5 mg melatonin is worth considering in patients with tuberous sclerosis complex and sleep disorder. ( J Child Neurol 2005;20:78—80).

Background: The aetiology of the learning difficulty in tuberous sclerosis is debated. It may be related to the amount of tubers in the brain or caused by the infantile spasms that occur in early life. Aims: To examine the relative contributions to final intelligence (IQ) made by both cerebral tubers and infantile spasms. Methods: As part of an epidemiological study of tuberous sclerosis in the south of England, patients were recruited who were able to undergo magnetic resonance imaging (MRI) without the need for an anaesthetic. Epilepsy history was determined by interview and review of clinical records. IQ was assessed using either Wechsler intelligence scales or Raven’s matrices. Results: A total of 41 patients consented to have an MRI scan. IQ scores were normally distributed about a mean of 91. Twenty six patients had a positive history of epilepsy, and 11 had suffered from infantile spasms. There was a significant relation between the number of tubers and IQ. Infantile spasm status partly confounded the relation between tubers and IQ, but did not render the relation statistically insignificant. The relation between infantile spasms and learning difficulty remained strong even when controlling for the number of tubers.

Lymphangioleiomyomatosis (LAM), characterized by alveolar smooth muscle proliferation and cystic destruction of lung parenchyma, can occur as a rare sporadic disease or as a complication of tuberous sclerosis (TSC). It is a cystic lung disease, usually generalized and progressive, may be extremely difficult to treat and has been considered to have a poor prognosis. It has almost exclusively been reported to present in women of childbearing age, most commonly with dyspnoea and pneumothorax. We reviewed the English literature from 1939 to 1997 for cases of LAM both with and without TSC, in order to document the prevalence, clinical features, investigations, treatment and outcome within and between these two groups. No study has yet determined the prevalence of LAM symptomatically within the general population, but it probably affects 1–3% of the TSC population. Patients with TSC often present with an insidious onset of dyspnoea whilst non-TSC patients present more commonly with acute breathlessness secondary to pneumothorax. Patients with TSC are also less likely to suffer from chylothorax. The age of onset of symptoms and of diagnosis are similar. LAM is rare in children and even less common in males in both groups. The natural course of LAM remains unclear and effect of treatment variable. Although symptomatic LAM is uncommon it causes a significant amount of morbidity and mortality both in the TSC and general population, but asymptomatic LAM is not uncommon in TSC. Further research is required to determine the natural history of this condition and to evaluate current treatment regimes.

BACKGROUND/AIMS—Tuberous sclerosis complex (TSC) has retinal and non-retinal ophthalmic manifestations. This study was designed to determine the prevalence of the ophthalmic manifestations and of refractive errors in a population of patients with TSC. METHODS—179 patients identified were in a prevalence study of TSC in the south of England and 107 of these agreed to full ophthalmic examination which was successful in 100. Ophthalmic examination included examination of the eyelids, cover test, examination of the irides, dilation funduscopy using both direct and indirect ophthalmoscopy, and refraction using retinoscopy. Myopia was defined as a spherical equivalent +0.5D. RESULTS—Retinal hamartomas were seen in 44 of the 100 patients. The commonest morphological type of hamartoma seen was the flat, translucent lesion in 31 of the 44 patients (70%). The multinodular "mulberry" lesion was seen in 24 of the 44 patients (55%) and the transitional type lesion was seen in four of the 44 patients (9%). Punched out areas of retinal depigmentation were seen in 39 of the 100 patients but only six of 100 controls. 27% of eyes were myopic, 22% were hyperopic, and 27% had astigmatism >0.75D. Of the non-retinal findings, 39 patients had angiofibromas of the eyelids, five had non-paralytic strabismus, and three had colobomas. CONCLUSION—Apart from the higher prevalence of flat retinal hamartomas, the findings of this study compare closely with previous large clinic based series of TSC patients. Refractive findings were similar to previous studies of a similarly aged non-TSC population. This is the first series to document the statistically significant association of punched out chorioretinal depigmentation with TSC and the authors believe that it should be looked for as an aid to diagnosis.

As a result of extreme clinical variability in tuberous sclerosis, with one well-documented example of non-penetrance, phenotypically normal siblings or children of patients with tuberous sclerosis are thought to be at increased risk of having children with the disease. We report that the case of apparent non-penetrance that was previously described is the result of two independent tuberous-sclerosis mutations in the same family.

Editor—Tuberous sclerosis complex (TSC) is a dominantly inherited disease of high penetrance, characterised pathologically by the presence of hamartomata in multiple organ systems. Well known clinical manifestations include epilepsy, learning difficulties, behavioural problems, and skin lesions. Many patients have renal lesions, usually angiomyolipomata (AML), which can cause clinical problems secondary to haemorrhage or by compression and replacement of healthy renal tissue, which rarely causes end stage renal failure.1 Cysts, polycystic renal disease, and renal carcinoma can also occur. Polycystic disease has an early onset clinically and is the result of large contiguous deletions on chromosome 16 affecting both the TSC2 gene and the gene for adult onset polycystic kidney disease.2Tuberous sclerosis complex exhibits genetic heterogeneity.3 Mutations in two recently identified genes, TSC1 at 9q34 and TSC2 at 16p13, each result in an apparently similar phenotype, although recent work has suggested that mutations in TSC2 may be associated with more severe …

OBJECTIVES--To establish the frequency of fits and mental retardation in an unbiased group of tuberous sclerosis patients. METHODS--Known tuberous sclerosis families with more than one affected person were ascertained for a genetic linkage study. A number of members were born after genetic counselling had been given after identification of the proband. These subjects were then carefully examined clinically and in many cases with cranial computerised tomography, renal ultrasound, and skeletal survey but not echocardiography. They provide an unbiased group of tuberous sclerosis patients and allow affected patients with normal intellect to be diagnosed. PATIENTS--Thirty-seven tuberous sclerosis families were ascertained and 26 patients born after the family proband were identified. RESULTS--Sixteen of these 26 patients suffered fits (62%) and 10 patients were mentally retarded (38%). CONCLUSIONS--A lower incidence of fits and mental retardation has been found in an unbiased sample of tuberous sclerosis patients. The lifetime risk for fits might be higher had we been able to follow the patients for longer. However, we believe these are more appropriate figures to use in genetic counselling for this disease.

Tuberous sclerosis (TSC) is a multisystem disorder encompassing a wide spectrum of pathological renal lesions. Renal involvement is commonly asymptomatic but can result in significant morbidity, and renal failure has been reported. The risk of renal failure in patients with TSC in the UK has not been defined.A survey of the 170 members of the European Dialysis and Transplant Association was carried out to identify and collect clinical information on patients with TSC in their renal replacement programme.Ten patients were identified as having end-stage renal failure (ESRF) and TSC, giving an incidence of 1% in patients with TSC and normal intellect. There was a wide spectrum of underlying pathology and clinical presentation within this group.ESRF is rare in TSC but does contribute to significant morbidity and mortality in this group.

The results of a therapeutic trial of the use of melatonin in patients with tuberous sclerosis complex who also have severe sleep problems are reported. We used a randomized double-blind placebo-controlled crossover design. Seven patients with confirmed diagnoses of tuberous sclerosis and significant sleep disorder were recruited. We employed three outcome measures: total sleep time, time to sleep onset, and number of awakenings. Patients treated with melatonin had a small but clinically significant improvement in total sleep time (mean improvement 0.55 hours, P

time. Unfortunately, in human populations these assumptions are frequently violated. The problem can be minimised by the use of techniques such as log-linear modelling but a high degree of accuracy in the estimate of numbers of missing cases should not be expected. We carried out a capture-recapture analysis of data collected in the survey of prevalence of tuberous sclerosis in Wessex. Cases had been identified from a large number of different sources. Data from these individual sources were pooled to construct three summary sources: cases identified by paediatricians; cases identified by other medical practitioners; and cases identified from other sources (for example, the Tuberous Sclerosis Association or Hospital Activity Analysis). We used the method described by Hook and Regal to first derive estimates for the total number of cases from each of the three possible two-source models and finally from all three sources. The figure shows the number of cases identified from each source and the overlap between sources. No cases were identified from all three sources. Maximum likelihood estimates are given for the total number of people with tuberous sclerosis in this population derived from each of the two-source models and from the three-source model. Dependency between sources was investigated by including terms for interaction between sources in the loglinear model; none of these terms was statistically significant. The Wessex survey originally identified 131 cases of tuberous sclerosis in a population of 3·4 million. The results of the capture-recapture analysis suggest that, despite the efforts of the investigators to locate all cases, more than half remained undetected. A revised estimate of prevalence, taking account of unascertained cases, is 8·8 per 100 000 population (95% CI 6·8–12·4). One implication is that many people with tuberous sclerosis do not receive either genetic counselling or specialist medical supervision.

SUMMARY Neurological complications and other causes of morbidity were studied in 122 of 131 individuals (64 males. 67 females) with tuberous sclerosis, in a population in which its prevalence was 1/26,500. Seizures occurred in 78 per cent, beginning at less than one year of age in 69 per cent (in more males than females in both cases) and after age 16 in 4 per cent. More males than females also had infantile spasms and persistent seizures. Learning disorder occurred in 53 per cent (also in more males), all with a history of seizures, and was strongly correlated with age at onset of seizures, type of seizure and outcome for seizure control. Of subjects with learning disorder. 85 per cent required supervision for daily living and 65 per cent had little or no language: 97 per cent were fully mobile. Hcmiparesis had occurred in eight of the 131, giant cell astrocytomas in nine, bilateral polycystic kidney disease in two. and haemorrhagic complication relating to renal angiomyolipomas in six. RESUME De la morbidite associee a la sclerose tubereuse: une etude de population. Les complications neurologiques et les autres causes de morbidite ont eteetudiees chez 122 parrni 131 patients (64 garcons, 67 filles) avec sclerose tubereuse. dans une population ou la prevalence etait de 1/26 500. II y avait des crises comitiales dans 78 pour cent des cas, debutant a un âge inferieur a un an dans 69 pour cent (avec plus de garcons que de filles clans les deux cas) et apres l'âge de 16 ans dans quatre pour cent. Egalement plus de garcons que de filles avaient presente des spasmes en flexion et des crises persistantes. Des troubles des apprentissages existaient dans 53 pour cent des cas (egalement plus frequents chez les garcons). tous avec un historique de crises et une forte correlation avec l'âge au debut des crises, le type des crises, et le devenir du controle de la comitialite. Parmi les sujets avec troubles d'apprentissage. 85 pour cent, exigeaient une surveillance constante pour la vie joumaliere et 65 pour cent avaient un langage peu developpe ou nul; 97 pour cent se deplacaient pleinemeni. Une hemiparesie etait presente dans huit des 131 cas, il y cu un astrocytome a cellules geantes dans neuf cas. des reins polykystiques bilateraux dans deux cas et des complications hemorragiques liees a une angiomyolipomatose renale dans six cas. ZUSAMMENFASSUNG Morbiditat bei tubetoser Hirnsklerose: cine Populalionssludie Bei 122 von 131 Patientcn (64 mannliche und 67 weibliche) mil tuberoser Hirnsklerose aus einer Population mil einer Haufigkeit von 1/26 500 wurden neurologische Komplikationen und andere Erkrankungsursachcn untersucht. Anfalle traten bei 78 Prozent auf, die bei 69 Prozent bereits im ersten Lebensjahr begannen (in beiden Fallen bei mehr Jungen als Madchen) und bei 4 Prozent nach dem 16. Lebensjahr. Auch bei den BNS Krampfen und den persistierenden Anfallsleiden war die Zahl der Jungen hoher als die der Madchen. Bei 53 Prozent fanden sich Lernstorungen (auch vorwiegend bei Jungen), allc hatten Anfalle in der Anamnese und es bestand eine enge Korrelation zum Alter bei Beginn der Anfalle, zur Art der Anfalle und zur Anfallskontrolle. Von den Patienten mit Lernproblemen brauchten 85 Prozent eine Betreuung im taglichen Leben und 65 Prozent konnten kaum oder gar nicht sprechen. 97 Prozent konnten sich uneingeschrankt bewegen. Acht der 131 Patienten hattcn einc Hcmiparese, neun eine bilateralc polyzystische Nierenerkrankung und sechs hamorrhagische Komplikationen in Verbindung mit renalen Angiomyelolipomen. RESUMEN Morbilidad asociada a esclerosis tiiberosa: estudio de poblacion. Se estudiaron las complicaciones neurologicas y otras causas de morbilidad en 122 de 131 individuos (64 varones y 67 hembras) con esclerosis tuberosa, en una poblacion en la que la prevalencia era de 1/26 500. Aparecieron convulsiones en el 78 por ciento iniciandose a menos de un ano de edad en el 69 por ciento (mas en varones que en hembras en ambos casos) y despues de los 16 en el 4 por ciento. Igualmcntc los espasmos infantiles y las convulsiones existentes se vieron mas en varones que en hembras. Alteraciones en el aprendizaje ocurrieron en el 53 por ciento (tambien mas en varones), todos con una historia de convulsiones y estaban fuertemente correlacionadas con la edad de inicio de las convulsiones, el tipo de convulsion y el curso del control de las mismas. De los individuos con alteraciones del aprendizaje, el 85 por ciento requirieron una supervision para su vida diaria y el 65 por ciento no tenian lenguaje o muy poco; el 97 por ciento tenian una movilidad completa. La hemiparesia estaba presente en ocho dc los 131 casos, astrocitomas de celulas gigantes en nueve, enfermedad poliquistica renal en dos y complicaciones hemorragicas en relation con angiomiolipomas de rinon en seis.

A search for children presenting with signs or symptoms of cardiac rhabdomyomas was made through members of the paediatric section of the British Cardiac Society in order to establish their birth incidence, presenting features, clinical course, and the frequency of a concurrent diagnosis of tuberous sclerosis. Fifteen children were identified and 12 had tuberous sclerosis (80%). Heart failure was the presentation in six, five of whom died; six presented because of a murmur and three because of arrhythmias. The prevalence of echocardiographic evidence of cardiac rhabdomyomas in a population of patients with tuberous sclerosis was established. Twenty individuals had echocardiography and eight had echodensities consistent with cardiac rhabdomyomas. It is concluded that the minimum birth incidence for children presenting because of the effects of cardiac rhabdomyomas is 1/326,000 and a minimum of 80% have tuberous sclerosis. In a population of patients with tuberous sclerosis a minimum of 60% under 18 years have cardiac rhabdomyomas.

Non-penetrance has not been reported in tuberous sclerosis when modern non-invasive investigations have been performed. We report a four generation family in which there was a subject with minimal expression and another with non-penetrance between a great grandfather and his great grandson. This situation highlights the need for full investigation of children of tuberous sclerosis patients before counselling a low recurrence risk for the disease.

Forty sets of parents and 24 sibs of patients with tuberous sclerosis were investigated by an extensive protocol, including clinical examination of skin, hair, and oral cavity, direct and indirect ophthalmoscopy, cranial CT scan, renal ultrasound, and a radiological skeletal survey. None of the clinical examinations provided evidence that any of the subjects was affected. Similarly, the cranial CT scan, renal ultrasound, and skeletal survey failed to identify any occult gene carriers. All of these investigations showed abnormalities in some parents but none was diagnostic. This study shows the difficulties in interpretation that these investigations may produce with consequent problems for genetic counselling. The study does not support the routine use of these tests. There are published reports where the diagnosis of tuberous sclerosis has been made in adults exclusively on a CT scan and an argument can be made for including this investigation. There is no indication for performing renal ultrasound nor skeletal x rays in parents who have normal clinical examinations.

1992-3, without a parallel increase in activity. Last year, providers' deadlines for issuing prices slipped several times, causing chaos to purchasers. East Birmingham's last contract was signed in August instead of the preceding March. The new regional edict is: "There are deadlines; we do not accept changes thereafter." Howard Shaw was less enthusiastic than his director of corporate management about the workings of the intemal market. "We're two months ahead of last year, but I'm not sure we've leamt that much. I don't think we've understood how to play the market, or even if the market's to be played because of the whole complexity of the system. We've got 20 units providing 50 specialties-for inpatients, day cases, and outpatients. There's a price and a volume for each of these, and you can have price and volume variance on all these contracts. So you've got this mass of data, and we can't make head or tail of it." His opinion was echoed by Robert Marriott. He did not think that you could decide at this stage whether the outcome of the reforms was good or bad. "Mostly it seems confusion-because of the demands being made on both purchasers and providers." Perhaps in a year's time things will be clearer.

Linkage analysis was undertaken in nineteen families with tuberous sclerosis by use of 26 polymorphic markers. All affected members fulfilled strict diagnostic criteria and unaffected members were rigorously investigated to confirm their status. Maximum lod scores were 1.20 for adenylate kinase 1 (AK1) at zero recombination and 3.85 for the ABO blood group at zero recombination (confidence limits 0-0.10). These findings support the assignment of the gene for tuberous sclerosis to the distal long arm of chromosome 9.