Abnormal frequency of ΔF508 mutation in neonatal transitory hypertrypsinaemia
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55 organisms within families could also be important but is not genetically determined. Such variables affect pulmonary, but not pancreatic, status. The evidence produced by Santis and colleagues, and by others,’ is consistent with the view that the &Dgr;F508 mutation is probably associated with severe disease in both the pancreas and the lungs. Our own preliminary observations suggest that other mutations affecting exon 10 should be regarded as equivalent to &Dgr;F508 (O’Rawe A, Dodge JA, unpublished). Not only do severe involvement of the lungs and the pancreas in CF tend to occur together, but also there is evidence that patients with milder pancreatic disease have lower sweat electrolyte values suggesting that mild and severe CF variants are not organ-specific. We should not be surprised at the fact that not all patients with a certain genetic abnormality behave in precisely the same way. Destruction of the exocrine pancreas is an end result of disordered physiology, in which duct obstruction occurs and is associated with chronic pancreatitis. The extent of pancreatic damage at particular ages will depend both on the underlying severity of the genetic disorder and on the location and number of ductules that happen to be blocked. All the genetic ingredients may be present but the rate of progress of the condition will depend on random, non-genetic factors within the organ itself. In infantile hypertonic pyloric stenosis, which also has a genetically determined predisposition, I have seen identical twins who were apparently discordant, the "unaffected" infant having radiologial evidence of pyloric hypertrophy but no vomiting. Similar cases have been recorded before. These infants shared both genes and environment. I concluded that individual physiological variables determined whether actual or only potential obstruction occurred.3 In biological systems it is not always reasonable to expect a uniform rate of progress among individuals. My point may be important because one consequence of accepting that outcomes in CF are entirely determined by gene mutations could be a fatalistic approach to management, in the belief that the genes would have the last word. The documented improvement in prognosis during the past two decades’ proves that progress can be substantially modified by non-genetic factors. Nuffield Department of Child Health, Queen’s University of Belfast, Institute of Clinical Science, Belfast BT12 6BJ, UK J. A. DODGE 1. Gaskin K, Gurwitz D, Dune P, et al. Improved respiratory prognosis m patients with cystic fibrosis with normal fat absorption J Pediatr 1982; 100: 857-62. 2 Davis PB, Hubbard VS, di Sant’Agnese PA Low sweat electrolytes in a patient with cystic fibrosis. Am J Med 1980, 69: 643-46 3 Dodge JA. Genetics of hypertrophic pyloric stenosis. Clinics Gastroenterol 1973, 2: 523-38. 4 British Paediatric Association Working Party on Cystic Fibrosis. Cystic fibrosis in the United Kingdom 1977-85: an improving picture Br Med J 1988, 297: 1599-602. Abnormal frequency of &Dgr;F508 mutation in neonatal transitory hypertrypsinaemia SIR,—As pointed out by Dumur et al’ heterozygosity for the cystic fibrosis (CF) &Dgr;F508 mutation is more frequent than expected2 in adults with chronic bronchial hypersecretion. This suggests that heterozygotes for CF may have some mild forms of the disease. Newborn babies with CF have abnormally high levels of immunoreactive trypsin (IRT) in serum, which is the basis for a screening test.3 Using the dried blood spots collected for CF screening we looked at carrier frequencies of dF 508 mutation in babies with mildly raised IRT concentrations. In our CF screening programme 08% of newborn babies have IRT concentrations of 600 µg/l on the 4th day of life, 0-3% being above 800 µg/l (Behring units).’ In the CF population 95% of neonates have an IRT above 800 p.g/1 on day 4 and above 600 I1g/1 on day 21, 5% of CF neonates having a normal IRT (false negative). Less than 1 in 15 000 non-CF babies have the same IRT pattern as babies with CF. From January to September, 1990, 28 000 babies were screened; 149 had an IRT on day 4 of 600 µg/l and below 600 µg/l on day 21. We identified 9 &Dgr;F508 heterozygotes, who were presumed not to have CF since, for ethical reasons, they would not be sweat-tested in the absence of persistent hypertrypsinaemia. The incidence of CF in our region is 1 in 3150 with a carrier frequency of CF of 1 in 28. In our CF population, the frequency of .’1F5o8 is slightly lower than the 70% usually reported for France,’ with an expected incidence of the .’1F 508 heterozygotes of 1 in 42. The frequency of .’1F 508 mutation reported here in a restricted population (9 in 149) is significantly higher (p < 0 01; corrected chi square) than expected. These .’1F 508 heterozygotes may have a predisposition to some mild biological abnormalities as early as the first days of life. Supported by Association Française de Lutte contre la Mucoviscidose. We thank Dr C. Ferec (Brest) for advice. Radioisotope Service, CHRU de Caen, 14033 Caen, France DOMINIQUE LAROCHE GEORGES TRAVERT 1 Dumur V, Lafitte JJ, Gervais R, et al. Abnormal distribution of cystic fibrosis &Dgr;F508 allele in adults with chronic bronchial hypersecretion. Lancet 1990, 335: 1340. 2 Kerem BS, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosis gene: genetic analysis. Science 1989, 245: 1073-80 3 Crossley JR, Elliott RB, Smith PA. Dried blood spot screening for cystic fibrosis in the newborn. Lancet 1979, i: 472-74 4 Travert G, Duhamel JF Neonatal screening for cystic fibrosis using trypsin radioimmunoassay in blood Arch Fr Pédiatr 1983; 40: 295-98 5 Cystic Fibrosis Genetic Analysis Consortium. Worldwide survey of the &Dgr;F508 mutation. Am J Hum Genet 1990, 47: 354-59. &bgr;(A4)-amyloid protein and parkinsonian- dementia complex of Guam SIR,—Intracellular neurofibrillary tangles are a common feature of Alzheimer’s disease (AD), older patients with Down’s syndrome, dementia pugilistica ("punch-drunk syndrome" of boxers) and the parkinsonian-dementia complex amyotrophic lateral sclerosis (PDG/ALS) that is endemic among the Chamorro people of Guam. The tangles in these disorders contain similar antigenic components,’ perhaps pointing to a common pathogenesis. The other major characteristic lesions associated with AD, the extracellular &bgr;(A4)-amyloid plaques, are thought to be absent in boxer’s dementia and PDG/ALS. However, immuno- histochemistry using antibodies to the &bgr;(A4)-amyloid protein component of plaque cores has revealed "diffuse" amyloid plaques in the brains of AD, Down’s syndrome, and to some extent, normal elderly control patients3.4 which are not detectable by conventional stains. We have, to our surprise, found diffuse &bgr;(A4)-amyloid plaques in the brains of boxers with dementia pugilistica.5 We wondered whether these plaques are present in the brains of PDG/ALS patients-a question of special interest in view of the realisation that AD is probably aetiologically heterogeneous6 and that both genetic and environmental factors are implicated. We have screened paraffin-embedded, formalin-fixed sections of temporal lobe tissue from 8 patients with PDG/ALS (6 males and 2 females, aged 33-66 years) using a monoclonal antibody (4D12/2/6) raised against residues 8-17 of the &bgr;-protein. The immunocytochemical techniques are described in detail elsewhere.’ 80% formic acid was used to pretreat the sections for 20 min to increase the antigenicity of the &bgr;-protein, and sections of AD brain were used as positive controls. All the AD control brains had intense staining of the &bgr;-protein deposits throughout the cortical ribbon and to some extent within the white-matter. Little or no trace of &bgr;-protein immunoreactivity was observed in any of the PDG/ALS cases. A limited amount of &bgr;(A4)-amyloid deposition has been observed in two old (> 65 years) PDG/ALS cases;’ however, the degree of deposition was consistent with that commonly found in normal ageing. 3 The cause of endemic PDG/ALS in Guam is unknown. Although clustering has been noted within families, no genetic component has yet been isolated, and epidemiological evidence strongly points to an exogenous or environmental caused One hypothesis is that the deficits in mineral metabolism result in the accumulation of calcium and aluminium deposits which may lead to neuronal degradation and neurofibrillary tangle formation.9 Another centres around the neurotoxic cycads in the Chamorro diet.8 The absence of &bgr;-amyloid immunoreactive plaques in
Transcript of Abnormal frequency of ΔF508 mutation in neonatal transitory hypertrypsinaemia
55
organisms within families could also be important but is not
genetically determined. Such variables affect pulmonary, but notpancreatic, status.The evidence produced by Santis and colleagues, and by others,’
is consistent with the view that the &Dgr;F508 mutation is probablyassociated with severe disease in both the pancreas and the lungs.Our own preliminary observations suggest that other mutationsaffecting exon 10 should be regarded as equivalent to &Dgr;F508(O’Rawe A, Dodge JA, unpublished). Not only do severe
involvement of the lungs and the pancreas in CF tend to occurtogether, but also there is evidence that patients with milderpancreatic disease have lower sweat electrolyte values suggestingthat mild and severe CF variants are not organ-specific.We should not be surprised at the fact that not all patients with a
certain genetic abnormality behave in precisely the same way.Destruction of the exocrine pancreas is an end result of disordered
physiology, in which duct obstruction occurs and is associated withchronic pancreatitis. The extent of pancreatic damage at particularages will depend both on the underlying severity of the geneticdisorder and on the location and number of ductules that happen tobe blocked. All the genetic ingredients may be present but the rate ofprogress of the condition will depend on random, non-genetic
factors within the organ itself. In infantile hypertonic pyloricstenosis, which also has a genetically determined predisposition, Ihave seen identical twins who were apparently discordant, the"unaffected" infant having radiologial evidence of pylorichypertrophy but no vomiting. Similar cases have been recordedbefore. These infants shared both genes and environment. I
concluded that individual physiological variables determinedwhether actual or only potential obstruction occurred.3 In biologicalsystems it is not always reasonable to expect a uniform rate ofprogress among individuals.
My point may be important because one consequence ofaccepting that outcomes in CF are entirely determined by genemutations could be a fatalistic approach to management, in thebelief that the genes would have the last word. The documented
improvement in prognosis during the past two decades’ proves thatprogress can be substantially modified by non-genetic factors.
Nuffield Department of Child Health,Queen’s University of Belfast,Institute of Clinical Science,Belfast BT12 6BJ, UK J. A. DODGE
1. Gaskin K, Gurwitz D, Dune P, et al. Improved respiratory prognosis m patients withcystic fibrosis with normal fat absorption J Pediatr 1982; 100: 857-62.
2 Davis PB, Hubbard VS, di Sant’Agnese PA Low sweat electrolytes in a patient withcystic fibrosis. Am J Med 1980, 69: 643-46
3 Dodge JA. Genetics of hypertrophic pyloric stenosis. Clinics Gastroenterol 1973, 2:523-38.
4 British Paediatric Association Working Party on Cystic Fibrosis. Cystic fibrosis in theUnited Kingdom 1977-85: an improving picture Br Med J 1988, 297: 1599-602.
Abnormal frequency of &Dgr;F508 mutation inneonatal transitory hypertrypsinaemia
SIR,—As pointed out by Dumur et al’ heterozygosity for thecystic fibrosis (CF) &Dgr;F508 mutation is more frequent than expected2in adults with chronic bronchial hypersecretion. This suggests thatheterozygotes for CF may have some mild forms of the disease.Newborn babies with CF have abnormally high levels ofimmunoreactive trypsin (IRT) in serum, which is the basis for ascreening test.3 Using the dried blood spots collected for CFscreening we looked at carrier frequencies of dF 508 mutation inbabies with mildly raised IRT concentrations.
In our CF screening programme 08% of newborn babies haveIRT concentrations of 600 µg/l on the 4th day of life, 0-3% beingabove 800 µg/l (Behring units).’ In the CF population 95% ofneonates have an IRT above 800 p.g/1 on day 4 and above 600 I1g/1 onday 21, 5% of CF neonates having a normal IRT (false negative).Less than 1 in 15 000 non-CF babies have the same IRT pattern asbabies with CF. From January to September, 1990, 28 000 babieswere screened; 149 had an IRT on day 4 of 600 µg/l and below 600µg/l on day 21. We identified 9 &Dgr;F508 heterozygotes, who werepresumed not to have CF since, for ethical reasons, they would not
be sweat-tested in the absence of persistent hypertrypsinaemia. Theincidence of CF in our region is 1 in 3150 with a carrier frequency ofCF of 1 in 28. In our CF population, the frequency of .’1F5o8 isslightly lower than the 70% usually reported for France,’ with anexpected incidence of the .’1F 508 heterozygotes of 1 in 42. The
frequency of .’1F 508 mutation reported here in a restricted population(9 in 149) is significantly higher (p < 0 01; corrected chi square) thanexpected. These .’1F 508 heterozygotes may have a predispositionto some mild biological abnormalities as early as the first days oflife.
Supported by Association Française de Lutte contre la Mucoviscidose. Wethank Dr C. Ferec (Brest) for advice.
Radioisotope Service,CHRU de Caen,14033 Caen, France
DOMINIQUE LAROCHEGEORGES TRAVERT
1 Dumur V, Lafitte JJ, Gervais R, et al. Abnormal distribution of cystic fibrosis &Dgr;F508allele in adults with chronic bronchial hypersecretion. Lancet 1990, 335: 1340.
2 Kerem BS, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosisgene: genetic analysis. Science 1989, 245: 1073-80
3 Crossley JR, Elliott RB, Smith PA. Dried blood spot screening for cystic fibrosis in thenewborn. Lancet 1979, i: 472-74
4 Travert G, Duhamel JF Neonatal screening for cystic fibrosis using trypsinradioimmunoassay in blood Arch Fr Pédiatr 1983; 40: 295-98
5 Cystic Fibrosis Genetic Analysis Consortium. Worldwide survey of the &Dgr;F508mutation. Am J Hum Genet 1990, 47: 354-59.
&bgr;(A4)-amyloid protein and parkinsonian-dementia complex of Guam
SIR,—Intracellular neurofibrillary tangles are a common featureof Alzheimer’s disease (AD), older patients with Down’s syndrome,dementia pugilistica ("punch-drunk syndrome" of boxers) and theparkinsonian-dementia complex amyotrophic lateral sclerosis
(PDG/ALS) that is endemic among the Chamorro people of Guam.The tangles in these disorders contain similar antigeniccomponents,’ perhaps pointing to a common pathogenesis. Theother major characteristic lesions associated with AD, theextracellular &bgr;(A4)-amyloid plaques, are thought to be absentin boxer’s dementia and PDG/ALS. However, immuno-
histochemistry using antibodies to the &bgr;(A4)-amyloid proteincomponent of plaque cores has revealed "diffuse" amyloid plaquesin the brains of AD, Down’s syndrome, and to some extent, normalelderly control patients3.4 which are not detectable by conventionalstains. We have, to our surprise, found diffuse &bgr;(A4)-amyloidplaques in the brains of boxers with dementia pugilistica.5 Wewondered whether these plaques are present in the brains ofPDG/ALS patients-a question of special interest in view of therealisation that AD is probably aetiologically heterogeneous6 andthat both genetic and environmental factors are implicated.We have screened paraffin-embedded, formalin-fixed sections of
temporal lobe tissue from 8 patients with PDG/ALS (6 males and 2females, aged 33-66 years) using a monoclonal antibody (4D12/2/6)raised against residues 8-17 of the &bgr;-protein. The
immunocytochemical techniques are described in detail elsewhere.’80% formic acid was used to pretreat the sections for 20 min toincrease the antigenicity of the &bgr;-protein, and sections of AD brainwere used as positive controls. All the AD control brains had intensestaining of the &bgr;-protein deposits throughout the cortical ribbonand to some extent within the white-matter. Little or no trace of
&bgr;-protein immunoreactivity was observed in any of the PDG/ALScases. A limited amount of &bgr;(A4)-amyloid deposition has beenobserved in two old (> 65 years) PDG/ALS cases;’ however, thedegree of deposition was consistent with that commonly found innormal ageing. 3The cause of endemic PDG/ALS in Guam is unknown.
Although clustering has been noted within families, no geneticcomponent has yet been isolated, and epidemiological evidencestrongly points to an exogenous or environmental caused Onehypothesis is that the deficits in mineral metabolism result in theaccumulation of calcium and aluminium deposits which may lead toneuronal degradation and neurofibrillary tangle formation.9Another centres around the neurotoxic cycads in the Chamorrodiet.8 The absence of &bgr;-amyloid immunoreactive plaques in
