Journal of the Royal Society of Medicine Volume 84 December 1991
699
Editorials
10 000. TS is renowned for its variable expression both between and within families and, because of this, various attempts have been made to draw up diagnostic criteria. The most recent revision of these criteria has just been published' and these are summarized in Table 1. The definitive features are individually diagnostic whereas more than one presumptive or suspicious feature has to be present before a diagnosis can be reached. The probability is greatly increased if the index case has an affected first degree relative. The most difficult diagnostic situation arising from these criteria is the individual with a seizure disorder, mental retardation and several depigmented patches but no other signs of TS. There have even been families reported where these remain the only findings in multiple affected persons. Such patients warrant thorough investigation to try and identify
included) remain sceptical in accepting white patches of whatever shape or form as diagnostic signs of TS in isolation. Nevertheless white patches are common and important early signs of TS-more than 90% of patients having more than four patches. These are sometimes only visible under ultraviolet light. Facial angiofibromas (adenoma sebaceum) are common and diagnostic. They are rarely present before 3 years of age and usually, but not always, present by the end of puberty. They are usually symmetrically distributed over the nose, cheeks and chin and can be a cosmetic problem. Laser therapy is proving a successful innovation in therapy alongside older treatments such as dermabrasion. Ungual fibromas occur in about 30% of the patients but are uncommon before puberty. One often sees ridging of the nails in the absence of fibromas. Shagreen patches are characteristically large single lesions on the back in the lumbosacral region but can be small areas resembling 'gooseflesh'. They have been reported in the absence of other signs of TS and so are listed in the presumptive category. One wonders whether such cases could represent a segmental form of TS due to a somatic mutation. Similarly some individuals with a single ungual fibroma or unilateral facial angiofibromas could be mosaic for a TS mutation. Forehead/scalp fibrous plaques are raised lesions histologically identical to facial angiofibromas and can be the first skin signs of the disorder. Cafe-aulait spots have in the past been recorded as a feature of TS but they are no more prevalent than in the
other features of TS. The depigmented patches themselves may provide some clues. These patches are dull-white in appearance (not snow-white as is usually the case in vitiligo) and can be polygonal (the commonest type), lance-ovate ('ash-leaf) or in multiple tiny 'confetti-like' patches. Whilst some dermnatologists feel that these TS lesions can be reliably distinguished from vitiligo and nevus depigmentosus on clinical and histological grounds, many other clinicians (myself
general population. The estimates of the frequency of mental retardation and epilepsy have been biased by the fact that it is these more severely affected individuals who come to medical attention. A recent study of family members ascertained for a genetic linkage study suggested that the incidence of mental retardation was nevertheless high - at 38% - and the incidence of a seizure disorder was 62%2. Infantile spasms are a frequent presenting
Tuberous sclerosis Tuberous sclerosis (TS) (syn epiloia, Bournevilles disease) is an autosomal dominant disorder first described in 1870 and best known for its cutaneous and neurological manifestations. Three careful British studies attempting complete ascertainment found an overall prevalence of the disorder of about 1 in 30 000, with a higher prevalence of 1 in 15 000 in the under-5 years age group, suggesting a birth incidence of 1 in
Table 1. Diagnostic features in tuberous sclerosis
Organ
Definitive
CNS
Cortical tuber
Retina Skin
Kidneys Heart Lungs Teeth
Subependymal nodules Giant cell astrocytomas Multiple phakomas Facial angiofibromas Ungual fibroma Forehead fibrous plaque Multiple angiomyolipomas (esp. if cysts also present)
Presumptive
Infantile spasms Other seizures
Single phakoma Confetti-like spots Shagreen patch
Depigmented macules
Single angiomyolipoma
Cysts
Multiple rhabdomyomas Lymphangiomatosis
Single rhabdomyoma Honeycomb image Enamel pits Fibromas
Gingiva Rectum Bones
Suspect
Hamartomatous polyps
Pseudocysts in phalanges Periosteal new bone (metacarpals/metatarsals)
0141-0768/91/ 120699-03/$02.00/0 © 1991 The Royal Society of Medicine
700
Journal of the Royal Society of Medicine Volume 84 December 1991
feature and the majority of such patients are subsequently mentally retarded3. These children also have a high frequency of hyperactive and autistic behaviour. The incidenwce of cerebral tumours is uncertain but probably no higher than 5-10%. These have a characteristic histology and position (subependymal giant cell astrocytomas) and grow during the first and second decades of life but rarely thereafter, though they can bleed spontaneously. The cranial CT scan.has been the method most employed for detecting intracranial lesions. The presence of two or more calcified subependymal nodules encroaching onto the lateral ventricles has been regarded as diagnostic of TS. Magnetic resonance imaging (MRI) scanning is less effective at detecting these lesions but is better at detecting cortical and subcortical tubers. Both are equally valuable iii detecting tumour development. Most reportsahave not found either CT or MRI appearances in early infancy helpful in predicting prognosis. One European study, did however find that the children -with normal intelligence had small isolated tubers mainly localized in the parietal and rolandic regions. Most children who did not speak had large or intermediate left temporal tubers. Those with. autism showed both frontal and posterior tubers. -All of the mentally retarded population showed multiple bilateral cortical tubers on MRI4. The classical retinal phakoma is a distinctive white, mulberry-shaped lesion found close to the optic disc. The Mayo Clinic experience suggests however that a more common retinal finding is a semi-transparent
lesion in the peripheral retina which can be difficult to identify. If looking for such lesions it is wise therefore for the patient to be examined by an experienced ophthalmologist using indirect ophthalmoscopy. Retinal lesions ate found in-50% of patients thus examined and are usually asymptomatic. Renal angiomyolipomas are most commonly asymptomatic but can present with flank pain, haematuria, hypertension or uraemia, usually in adult life. They may be found on imaging in about 50% of patients and have a predilection for female patients. Renal cysts have been found in 20% patients and renal carcinoma has also been reported but is fortunately rare. Pulmonary involvement -is rare and almost' confined to women in the third or fourth decade. Cardiac rhabdomyomas are common - found in 60% of affected children but < 20% of adults on echocardiography - but usually asymptomatic. They can be present before CT scan changes and hence echocardiography is a useful investigation in the infant presenting with infantile spasms. Serial echocardiograms have demonstrated some rhabdomyomas decreasing in size in infancy and even disappearing5. Dental enamel pits are a well recognized clinical feature and some studies have found theme to be present in the large majority of adult patients though they are more difficult to identify in the primary dentition. Rectal polyps are hamartomas found in 14 out of 18 mentally retarded TS patients in a recent
study. They were asymptomatic6.
There are numerous other manifestations reported
in TS patients and these are well summarized in
Gomez's monograph and the recently published
symposium"7.
There is great variability in expression within families so that a mildly affected parent can have a severely retarded child. In some families there appears
to be a clustering of features so that, for example, renal complications, cardiac tumours or cerebral tumours are more frequent than one might have expected. The diagnostic criteria provide useful guidelines for the clinician and emphasize that a thorough clinical examination is essential to exclude the diagnosis in anyone at risk. How often radiological examination is needed is uncertain. In the author's experience very few gene carriers will not have some skin signs of the disorder -although there are a few undoubted individuals who only have evidence of TS on cranial imaging8. It is exceptionally rare for renal ultrasound to detect lesions in an at-risk individual with no other signs though there has been a recent report suggesting that asymptomatic cardiac rhabdomiyomas detected radiologically can be the only sign in the parent of an affected child9. It seems very unlikely that this is a common occurrence in view of the-fact that it is rare for clinically normal parents to have a second affected child. The mutation rate in TS is high and 60-70% cases seem ;to represent new mutations. Penetrance of the gene is high although variability in expression is great as exemplified by a recent case report of a man Who developed an ungual fibroma in his forties having been previously reassured that he was not a gene carrier following a normal clinical ex ation (including ultraviolet light) and a normal cranial CT scan and normal renal ultra. sound examination'0. It ia difficult to know how, far to investigate the parents of an affected child. A thorough clinical examination including ophthalmoscopy and ultraviolet light examiation xs manatory and the most useful-further investigation isa cranial CT scan. Although MRI is more sensitiv6thali CT, CT is more specific and potentially less confusingl in interpretation. If these investigations are normal and even if the case is pursued further with normal renal imaging and normal echocardiography, I would still counsel a recurrence risk of- about 2% because of reduced and age-dependant penetrance- and the likelihood that germ-line mosaicioocurs. If a parent is affected, the recurrence risk is) 50%. Currently, prenatal diagnosis is only.- possible by fetal echocardiography and such examination will have a high rate of false negatives and is probably not reliable before 26 weeks. . What is the underlying genetic defect in TS? Changes in glycoproteins and proteoglycans are found in several TS tissues. Alterations in the glycosylation of fibronectin and in the N-sulphation of heparin sulphate have been established but the relationship of these findings to pathogenesis remains uncertain although the structure of the extracellular matrix influences cell migration and disordere4 neurgnal migration is a feature of TS. It is argued tha, some TS lesions could be explained on the basis of disturbed neural crest migration. Cell differentiation. is also abnormal in TS and it is possible that the primary mutation in TS involves a molecule imortant for the migration of neuronal precursor cells and that such cells may be initrinsically abnormal and fail to differentiate normally. Further studies in developmental neurobiology and in biochemistry may reveal possible candidate genes for the TS mutation. The reverse genetic approach has been successful in identifying the genes responsible for a number of single gene disorders but the TS gene is proving elusive. The first breakthrough was the demontration
Journal of the Royal Society of Medicine Volume 84 December 1991
of genetic linkage of the TS gene to the ABO blood group suggesting a locus on chromosome 911. Unfortunately not all TS families seem to have a mutation in a chromosome 9 gene and the identification of two cases of TS with chromosomnal alterations involving chromosomes 11 and 12 have provided evidence for loci on these chromosomes. There has been some evidence from genetic linkage studies to support these suggestions. Are there therefore at least three different TS genes? It seems possible that this is the case on current evidence and if so it will make the finer mapping of these loci and subsequent isolation of the genes a very difficult task. The development of more informative DNA polymorphisms and a strong international collaborative research strategy means that the situation should become clearer in the next couple of years. It will be fascinating to see whether there is any correlation between the clinical phenotype and the genetic locus. Some researchers have claimed that their 'chromosome 9' families tend to have a milder phenotype in terms of mental retardation than the 'non-9' families but the data are very limited and such is the variability within families that I remain sceptical. The isolation of the genes responsible for TS would also allow more reliable carrier detection and prenatal diagnosis. There would probably be a considerable demand for prenatal diagnosis given the highly distressing nature of the disorder with many of the affected children being mentally retarded, having seizures that are difficult to control and showing hyperactive and autistic behaviour. Some of these children die prematurely in prolonged seizures or from brain tumours. Mildly affected individuals usually have a normal lifespan, although some patients have died from renal failure or brain tumours. The mentally normal adult with TS can be reassured that the risks of developing such complications is low though they
Insulin - sniffing for jabbing
The sensational disclosure' from the Charing Cross Hospital that an oral preparation of insulin under investigation had been spiked with glibenclamide2 illustrates the pressure on research workers to find an alternative to injections for diabetics who need insulin. The horror of needles is high on the list of anxieties of people who have just been told they have diabetes. Their initial fear usually fades after a few weeks of self-injection and is replaced by concern over hypoglycaemic attacks (hypos). There is understandable disquiet at the prospect of losing one's self-control and possibly one's driving licence as a result of a low plasma glucose concentration. Hypos affect those with the best-controlled diabetes3 and once bitten they may be reluctant to aim at very tight metabolic control, which by a nasty twist reduces the warning signals of hypoglycaemia4. Traditionally insulin has been given by twice daily injections of a mixture of quick and slow-acting
701
should be advised about the risk of transmitting the disorder and the potential for a more severely affected child. A E Fryer Consultant Clinical Geneticist Royal Liverpool Hospital PO Box 147, Liverpool L69 3BX
References 1 Gomez MR. Phenotypes ofthe tuberous sclerosis complex with a revision of diagnostic criteria. Ann NYAcad Sci 1991;615:1-7 2 Webb DW, Fryer AE, Osborne JP. On the incidence of fits and mental retardation in tuberous sclerosis. J Med Genet 1991;28:395-7 3 Riikonen R, Simell 0. Tuberous sclerosis and infantile spasms. Dev Med Child Neurol 1990;32:203-9 4 Curatolo P, Cusmai R, Cortesi, et al. Neuropsychiatric aspects of tuberous sclerosis. Ann NY Acad Sci 1991;615:8-16 5 Wallace G, Smith HC, Watson GH, Rimmer S, D'Souza SW. Tuberous sclerosis presenting with fetal and neonatal cardiac tumours. Arch Dis Child 1990;65:377-9 6 Gould SR. Hamatomatous rectal polyps are common in tuberous sclerosis. Ann NY Acad Sci 1991;615:71-80 7 Gomez MR, ed. Tuberous sclerosis, 2nd edn. New York: Raven Press, 1988 8 Fryer AE, Osborne JP. The value of investigation for genetic counselling in tuberous sclerosis. J Med Genet 1990;27:217-23 9 Al-Gazali LI, Arthur RJ, Lamb JT, et al. Diagnostic and counselling difficulties using a fully comprehensive screening protocol for families at risk for tuberous sclerosis. J Med Genet 1989;26:694-703 10 Webb DW, Osborne JP. Non-penetrance in tuberous sclerosis. J Med Genet 1991;28:417-19 11 Fryer AE, Chalmers A, Connor JM, et aL Evidence that the gene for tuberous sclerosis is on chromosome 9. Lancet 1987;i:659-61
varieties hopefully designed to correspond with mealtimes. Insulin delivery has now been streamlined by the introduction of the pen injector which can be used without embarrassment in work-place orrestaurant5. In order to make mealtimes more flexible, people are prepared to inject themselves three times a day with soluble insulin, together with a bedtime injection of basal 'slow' insulin. In the non-diabetic state, serum insulin concentration rises within a few minutes of eating and once the blood glucose has returned to normal, insulin secretion is rapidly switched off. Neither twice daily mixtures nor multiple injections get round the problem that subcutaneous insulin (even the cleverlynamed Actrapid) is absorbed more slowly than food from the gut. A bolus of soluble insulin has no appreciable biological effect for 30 min6 and peaks an hour or two after food has been absorbed. People overcome the mismatch between food absorption and the uptake of injected insulin by taking sizeable snacks between meals. These cause unhappiness, particularly if people are trying to lose weight. Nasally administered insulin has been under investigation for over 10 years with efforts concentrating
0141-0768/91/ 120701-02/$02.00/0 © 1991 The Royal Society of Medicine
699
Editorials
10 000. TS is renowned for its variable expression both between and within families and, because of this, various attempts have been made to draw up diagnostic criteria. The most recent revision of these criteria has just been published' and these are summarized in Table 1. The definitive features are individually diagnostic whereas more than one presumptive or suspicious feature has to be present before a diagnosis can be reached. The probability is greatly increased if the index case has an affected first degree relative. The most difficult diagnostic situation arising from these criteria is the individual with a seizure disorder, mental retardation and several depigmented patches but no other signs of TS. There have even been families reported where these remain the only findings in multiple affected persons. Such patients warrant thorough investigation to try and identify
included) remain sceptical in accepting white patches of whatever shape or form as diagnostic signs of TS in isolation. Nevertheless white patches are common and important early signs of TS-more than 90% of patients having more than four patches. These are sometimes only visible under ultraviolet light. Facial angiofibromas (adenoma sebaceum) are common and diagnostic. They are rarely present before 3 years of age and usually, but not always, present by the end of puberty. They are usually symmetrically distributed over the nose, cheeks and chin and can be a cosmetic problem. Laser therapy is proving a successful innovation in therapy alongside older treatments such as dermabrasion. Ungual fibromas occur in about 30% of the patients but are uncommon before puberty. One often sees ridging of the nails in the absence of fibromas. Shagreen patches are characteristically large single lesions on the back in the lumbosacral region but can be small areas resembling 'gooseflesh'. They have been reported in the absence of other signs of TS and so are listed in the presumptive category. One wonders whether such cases could represent a segmental form of TS due to a somatic mutation. Similarly some individuals with a single ungual fibroma or unilateral facial angiofibromas could be mosaic for a TS mutation. Forehead/scalp fibrous plaques are raised lesions histologically identical to facial angiofibromas and can be the first skin signs of the disorder. Cafe-aulait spots have in the past been recorded as a feature of TS but they are no more prevalent than in the
other features of TS. The depigmented patches themselves may provide some clues. These patches are dull-white in appearance (not snow-white as is usually the case in vitiligo) and can be polygonal (the commonest type), lance-ovate ('ash-leaf) or in multiple tiny 'confetti-like' patches. Whilst some dermnatologists feel that these TS lesions can be reliably distinguished from vitiligo and nevus depigmentosus on clinical and histological grounds, many other clinicians (myself
general population. The estimates of the frequency of mental retardation and epilepsy have been biased by the fact that it is these more severely affected individuals who come to medical attention. A recent study of family members ascertained for a genetic linkage study suggested that the incidence of mental retardation was nevertheless high - at 38% - and the incidence of a seizure disorder was 62%2. Infantile spasms are a frequent presenting
Tuberous sclerosis Tuberous sclerosis (TS) (syn epiloia, Bournevilles disease) is an autosomal dominant disorder first described in 1870 and best known for its cutaneous and neurological manifestations. Three careful British studies attempting complete ascertainment found an overall prevalence of the disorder of about 1 in 30 000, with a higher prevalence of 1 in 15 000 in the under-5 years age group, suggesting a birth incidence of 1 in
Table 1. Diagnostic features in tuberous sclerosis
Organ
Definitive
CNS
Cortical tuber
Retina Skin
Kidneys Heart Lungs Teeth
Subependymal nodules Giant cell astrocytomas Multiple phakomas Facial angiofibromas Ungual fibroma Forehead fibrous plaque Multiple angiomyolipomas (esp. if cysts also present)
Presumptive
Infantile spasms Other seizures
Single phakoma Confetti-like spots Shagreen patch
Depigmented macules
Single angiomyolipoma
Cysts
Multiple rhabdomyomas Lymphangiomatosis
Single rhabdomyoma Honeycomb image Enamel pits Fibromas
Gingiva Rectum Bones
Suspect
Hamartomatous polyps
Pseudocysts in phalanges Periosteal new bone (metacarpals/metatarsals)
0141-0768/91/ 120699-03/$02.00/0 © 1991 The Royal Society of Medicine
700
Journal of the Royal Society of Medicine Volume 84 December 1991
feature and the majority of such patients are subsequently mentally retarded3. These children also have a high frequency of hyperactive and autistic behaviour. The incidenwce of cerebral tumours is uncertain but probably no higher than 5-10%. These have a characteristic histology and position (subependymal giant cell astrocytomas) and grow during the first and second decades of life but rarely thereafter, though they can bleed spontaneously. The cranial CT scan.has been the method most employed for detecting intracranial lesions. The presence of two or more calcified subependymal nodules encroaching onto the lateral ventricles has been regarded as diagnostic of TS. Magnetic resonance imaging (MRI) scanning is less effective at detecting these lesions but is better at detecting cortical and subcortical tubers. Both are equally valuable iii detecting tumour development. Most reportsahave not found either CT or MRI appearances in early infancy helpful in predicting prognosis. One European study, did however find that the children -with normal intelligence had small isolated tubers mainly localized in the parietal and rolandic regions. Most children who did not speak had large or intermediate left temporal tubers. Those with. autism showed both frontal and posterior tubers. -All of the mentally retarded population showed multiple bilateral cortical tubers on MRI4. The classical retinal phakoma is a distinctive white, mulberry-shaped lesion found close to the optic disc. The Mayo Clinic experience suggests however that a more common retinal finding is a semi-transparent
lesion in the peripheral retina which can be difficult to identify. If looking for such lesions it is wise therefore for the patient to be examined by an experienced ophthalmologist using indirect ophthalmoscopy. Retinal lesions ate found in-50% of patients thus examined and are usually asymptomatic. Renal angiomyolipomas are most commonly asymptomatic but can present with flank pain, haematuria, hypertension or uraemia, usually in adult life. They may be found on imaging in about 50% of patients and have a predilection for female patients. Renal cysts have been found in 20% patients and renal carcinoma has also been reported but is fortunately rare. Pulmonary involvement -is rare and almost' confined to women in the third or fourth decade. Cardiac rhabdomyomas are common - found in 60% of affected children but < 20% of adults on echocardiography - but usually asymptomatic. They can be present before CT scan changes and hence echocardiography is a useful investigation in the infant presenting with infantile spasms. Serial echocardiograms have demonstrated some rhabdomyomas decreasing in size in infancy and even disappearing5. Dental enamel pits are a well recognized clinical feature and some studies have found theme to be present in the large majority of adult patients though they are more difficult to identify in the primary dentition. Rectal polyps are hamartomas found in 14 out of 18 mentally retarded TS patients in a recent
study. They were asymptomatic6.
There are numerous other manifestations reported
in TS patients and these are well summarized in
Gomez's monograph and the recently published
symposium"7.
There is great variability in expression within families so that a mildly affected parent can have a severely retarded child. In some families there appears
to be a clustering of features so that, for example, renal complications, cardiac tumours or cerebral tumours are more frequent than one might have expected. The diagnostic criteria provide useful guidelines for the clinician and emphasize that a thorough clinical examination is essential to exclude the diagnosis in anyone at risk. How often radiological examination is needed is uncertain. In the author's experience very few gene carriers will not have some skin signs of the disorder -although there are a few undoubted individuals who only have evidence of TS on cranial imaging8. It is exceptionally rare for renal ultrasound to detect lesions in an at-risk individual with no other signs though there has been a recent report suggesting that asymptomatic cardiac rhabdomiyomas detected radiologically can be the only sign in the parent of an affected child9. It seems very unlikely that this is a common occurrence in view of the-fact that it is rare for clinically normal parents to have a second affected child. The mutation rate in TS is high and 60-70% cases seem ;to represent new mutations. Penetrance of the gene is high although variability in expression is great as exemplified by a recent case report of a man Who developed an ungual fibroma in his forties having been previously reassured that he was not a gene carrier following a normal clinical ex ation (including ultraviolet light) and a normal cranial CT scan and normal renal ultra. sound examination'0. It ia difficult to know how, far to investigate the parents of an affected child. A thorough clinical examination including ophthalmoscopy and ultraviolet light examiation xs manatory and the most useful-further investigation isa cranial CT scan. Although MRI is more sensitiv6thali CT, CT is more specific and potentially less confusingl in interpretation. If these investigations are normal and even if the case is pursued further with normal renal imaging and normal echocardiography, I would still counsel a recurrence risk of- about 2% because of reduced and age-dependant penetrance- and the likelihood that germ-line mosaicioocurs. If a parent is affected, the recurrence risk is) 50%. Currently, prenatal diagnosis is only.- possible by fetal echocardiography and such examination will have a high rate of false negatives and is probably not reliable before 26 weeks. . What is the underlying genetic defect in TS? Changes in glycoproteins and proteoglycans are found in several TS tissues. Alterations in the glycosylation of fibronectin and in the N-sulphation of heparin sulphate have been established but the relationship of these findings to pathogenesis remains uncertain although the structure of the extracellular matrix influences cell migration and disordere4 neurgnal migration is a feature of TS. It is argued tha, some TS lesions could be explained on the basis of disturbed neural crest migration. Cell differentiation. is also abnormal in TS and it is possible that the primary mutation in TS involves a molecule imortant for the migration of neuronal precursor cells and that such cells may be initrinsically abnormal and fail to differentiate normally. Further studies in developmental neurobiology and in biochemistry may reveal possible candidate genes for the TS mutation. The reverse genetic approach has been successful in identifying the genes responsible for a number of single gene disorders but the TS gene is proving elusive. The first breakthrough was the demontration
Journal of the Royal Society of Medicine Volume 84 December 1991
of genetic linkage of the TS gene to the ABO blood group suggesting a locus on chromosome 911. Unfortunately not all TS families seem to have a mutation in a chromosome 9 gene and the identification of two cases of TS with chromosomnal alterations involving chromosomes 11 and 12 have provided evidence for loci on these chromosomes. There has been some evidence from genetic linkage studies to support these suggestions. Are there therefore at least three different TS genes? It seems possible that this is the case on current evidence and if so it will make the finer mapping of these loci and subsequent isolation of the genes a very difficult task. The development of more informative DNA polymorphisms and a strong international collaborative research strategy means that the situation should become clearer in the next couple of years. It will be fascinating to see whether there is any correlation between the clinical phenotype and the genetic locus. Some researchers have claimed that their 'chromosome 9' families tend to have a milder phenotype in terms of mental retardation than the 'non-9' families but the data are very limited and such is the variability within families that I remain sceptical. The isolation of the genes responsible for TS would also allow more reliable carrier detection and prenatal diagnosis. There would probably be a considerable demand for prenatal diagnosis given the highly distressing nature of the disorder with many of the affected children being mentally retarded, having seizures that are difficult to control and showing hyperactive and autistic behaviour. Some of these children die prematurely in prolonged seizures or from brain tumours. Mildly affected individuals usually have a normal lifespan, although some patients have died from renal failure or brain tumours. The mentally normal adult with TS can be reassured that the risks of developing such complications is low though they
Insulin - sniffing for jabbing
The sensational disclosure' from the Charing Cross Hospital that an oral preparation of insulin under investigation had been spiked with glibenclamide2 illustrates the pressure on research workers to find an alternative to injections for diabetics who need insulin. The horror of needles is high on the list of anxieties of people who have just been told they have diabetes. Their initial fear usually fades after a few weeks of self-injection and is replaced by concern over hypoglycaemic attacks (hypos). There is understandable disquiet at the prospect of losing one's self-control and possibly one's driving licence as a result of a low plasma glucose concentration. Hypos affect those with the best-controlled diabetes3 and once bitten they may be reluctant to aim at very tight metabolic control, which by a nasty twist reduces the warning signals of hypoglycaemia4. Traditionally insulin has been given by twice daily injections of a mixture of quick and slow-acting
701
should be advised about the risk of transmitting the disorder and the potential for a more severely affected child. A E Fryer Consultant Clinical Geneticist Royal Liverpool Hospital PO Box 147, Liverpool L69 3BX
References 1 Gomez MR. Phenotypes ofthe tuberous sclerosis complex with a revision of diagnostic criteria. Ann NYAcad Sci 1991;615:1-7 2 Webb DW, Fryer AE, Osborne JP. On the incidence of fits and mental retardation in tuberous sclerosis. J Med Genet 1991;28:395-7 3 Riikonen R, Simell 0. Tuberous sclerosis and infantile spasms. Dev Med Child Neurol 1990;32:203-9 4 Curatolo P, Cusmai R, Cortesi, et al. Neuropsychiatric aspects of tuberous sclerosis. Ann NY Acad Sci 1991;615:8-16 5 Wallace G, Smith HC, Watson GH, Rimmer S, D'Souza SW. Tuberous sclerosis presenting with fetal and neonatal cardiac tumours. Arch Dis Child 1990;65:377-9 6 Gould SR. Hamatomatous rectal polyps are common in tuberous sclerosis. Ann NY Acad Sci 1991;615:71-80 7 Gomez MR, ed. Tuberous sclerosis, 2nd edn. New York: Raven Press, 1988 8 Fryer AE, Osborne JP. The value of investigation for genetic counselling in tuberous sclerosis. J Med Genet 1990;27:217-23 9 Al-Gazali LI, Arthur RJ, Lamb JT, et al. Diagnostic and counselling difficulties using a fully comprehensive screening protocol for families at risk for tuberous sclerosis. J Med Genet 1989;26:694-703 10 Webb DW, Osborne JP. Non-penetrance in tuberous sclerosis. J Med Genet 1991;28:417-19 11 Fryer AE, Chalmers A, Connor JM, et aL Evidence that the gene for tuberous sclerosis is on chromosome 9. Lancet 1987;i:659-61
varieties hopefully designed to correspond with mealtimes. Insulin delivery has now been streamlined by the introduction of the pen injector which can be used without embarrassment in work-place orrestaurant5. In order to make mealtimes more flexible, people are prepared to inject themselves three times a day with soluble insulin, together with a bedtime injection of basal 'slow' insulin. In the non-diabetic state, serum insulin concentration rises within a few minutes of eating and once the blood glucose has returned to normal, insulin secretion is rapidly switched off. Neither twice daily mixtures nor multiple injections get round the problem that subcutaneous insulin (even the cleverlynamed Actrapid) is absorbed more slowly than food from the gut. A bolus of soluble insulin has no appreciable biological effect for 30 min6 and peaks an hour or two after food has been absorbed. People overcome the mismatch between food absorption and the uptake of injected insulin by taking sizeable snacks between meals. These cause unhappiness, particularly if people are trying to lose weight. Nasally administered insulin has been under investigation for over 10 years with efforts concentrating
0141-0768/91/ 120701-02/$02.00/0 © 1991 The Royal Society of Medicine
