1086
ACETYLCHOLINESTERASE ACTIVITIES IN ADRENAL TISSUE OBTAINED AT NECROPSY FROM ALZHEIMER’S PATIENTS AND CONTROLS
Results are given as mean (SEM). *nmol acetylthiocholine hydrolysed per mm; U test
tp < 05, tpO 005,
Mann
Whitney
system, such as sympathetic ganglia, to see if they are similarly affected in AD. These results could have implications for the use of the peripheral nervous system as donor tissue for brain transplants aimed at restoring neuronal pathways destroyed by neurodegenerative disease. Autografts seem to have little chance of survival in patients with AD since the graft tissue itself may be affected by the disease. Investigations in animals have demonstrated that AChE is secreted from the adrenal medulla.2 Reduced levels of soluble AChE in the adrenal gland in AD could therefore result in reduced secretion of AChE from the gland into the blood. However, there have been reports that plasma AChE activities are increased in patients with AD.4 Secretion of AChE from forebrain regions also seems to be abnormal in AD, leading to lower levels in ventricular cerebrospinal fluid.6 Hence AD may be associated with a defect in the secretion of AChE. The physiological significance of altered AChE secretion is at present unclear, especially in the peripheral nervous system, but there is evidence that AChE may have a neuromodulatory role in the central nervous system.7
transketolase were measured in erythrocyte haemolysates without and with an excess thiamine pyrophosphate (TPP).5 The % activation (TPP effect) is an index of thiamine status. In our laboratory, as elsewhere, TPP effect values above 15% indicate moderate-to-severe thaimine deficiency. 9 patients (23%) were thiamine deficient on this criterion, and 8 of these 9 were receiving zidovudine. Wernicke’s encephalopathy can be prevented if thiamine supplementation is given early enough in the course of the disease. The four reports of Wernicke’s encephalopathy in AIDS patients were post-mortem findings; neurological symptoms indicative of Wernicke’s encephalopathy had not been apparent before death and thiamine supplements had not been administered. Our results suggest that substantial numbers of patients with AIDS or AIDS-related complex are thiamine deficient and at risk of Wernicke’s encephalopathy. Thiamine supplementation in HIVpositive patients might be helpful. Laboratory of Neurochemistry, Centre de Recherche André-Viallet,
Microbiology Service, and Haematology Service, Hôpital Saint-Luc, Montreal, Quebec H2X 3J4, Canada
Davtyan DG, Vinters HV. Wemicke’s encephalopathy in AIDS patient treated with zidovudine. Lancet 1987; i: 919-20. 2. Foresti V, Confalonieri F. Wernicke’s encephalopathy in AIDS. Lancet 1987; i: 1499. 3. Lindboe CF, Loberg EM. Wernicke’s encephalopathy in non-alcoholics: an autopsy study. J Neurol Sci 1989; 90: 125-29. 4. Schwenk J, Gosztonyl G, Thieranf P, Iglesias J, Langer E. Wernicke’s encephalopathy in two patients with acquired immunodeficiency syndrome. J Neurol 1990; 7: 445-47. 5. Butterworth RF. Thiamine malnutrition and brain development. In: Current topics in nutrition and disease, vol XVI. New York. Alan R. Liss, 1987: 287-304. 1.
Department of Physiology, Royal Free Hospital School of Medicine, Department of Neuropathology, Radcliffe Infirmary,
BRENDAN MCDONALD
Oxford
1. Averback P. Two new lesions in Alzheimer’s disease. Lancet
2. 3.
1983; ii. 1203.
Somogyi P, Chubb IW, Smith AD. A possible structural basis for the extracellular release of acetylcholinesterase. Proc R Soc B 1975; 191: 271-83. Smith AD, Cuello AC. Alzheimer’s disease and acetylcholinesterase-containing
Lancet 1984; i: 513. Z. Cholinesterase and its molecular forms in pathological states. Progr Neurobiol 1988; 31: 311-30. 5. Appleyard ME, McDonald B, Benjamin L Presence of a soluble form of acetylcholinesterase m human ocular fluids. Br J Ophthalmol 1991; 75: 276-79. 6. Appleyard ME, Smith AD, Berman P, et al. Cholinesterase activities in cerebrospinal fluid of patients with senile dementia of the Alzheimer type. Brain 1987; 110: 1309-22. 7. Appleyard ME, Jahnsen H. Non-cholinergic effect of acetylcholinesterase upon the membrane properties of mammalian cerebellar Purkinje cells. Eur J Neurosci 1989; neurons.
4.
Rakonczay
(suppl 2): 129.
Thiamine
Zidovudine for HIV enteropathy
MARGARET E. APPLEYARD
London NW3 2PF, UK
deficiency in AIDS
SIR,-Four recent independent reports have described neuropathological changes (mammillary body atrophy, perivascular haemorrhagic lesions) characteristic of Wernicke’s encephalopathy in patients with AIDS.1 No patient was alcoholic and a diagnosis of Wernicke’s encephalopathy had not been entertained before death. Wernicke’s encephalopathy results from thiamine deficiency, generally
consequence of chronic other conditions associated with grossly impaired nutrition. Severe nutritional deficiencies are common in AIDS. These findings prompted us to evaluate thiamine status in patients with AIDS. 39 patients (36 male, 3 female; aged 22-67) with AIDS or AIDS-related complex were studied at various stages of the disease. In no case was there a history of alcohol abuse, nor were there any neurological symptoms (ophthalmoplegia, ataxia) suggestive of Wernicke’s encephalopathy. None was taking thiamine supplements. Thiamine status was measured by transketolase activation assay. Activities of the thiamine-dependent enzyme as
a
alcoholism, gastrointestinal disease,
or
ROGER F. BUTTERWORTH CHRISTIANE GAUDREAU JEAN VINCELETTE ANNE-MARIE BOURGAULT FRANÇOIS LAMOTHE ANNE-MARIE NUTINI
SIR,-A 22-year-old homosexual man was enrolled in a prospective study of nutrition in HIV infection. 3 months earlier he had seroconverted in association with primary HIV illness. Since then he had been well, except for occasional mild diarrhoea. His CD4 count was 651/)il and the CD8 count was 1260/ul. He was HIV p24 antigen negative but with a (32 microblobulin of 3-5 mg/1 A biochemical screen indicated possible (normal 0-2), serum retinol 1 ’3 Ilffiol/l (1 4-40), vitamin B12 44 pmol/1 (110-700), folate 6-8 nmol/1 (6-8-38-5), and ferritin 45 pmol/1 (55-880). The peripheral blood film and haemoglobin were normal. Proximal gut function was tested by the 14C-triolein breath test and shown to be abnormal (triolein exhaled per hour as 14C02 was 0’ 1 %, normal > 2-6%). Endoscopy and biopsy of the distal second part of the duodenum indicated partial villous atrophy with mildly increased intraepithelial lymphocytes and diffuse moderate-grade chronic inflammatory infiltrate in the lamina propria. These results are consistent with HIV enteropathy.l,2 Zidovudine 400 mg daily and monthly vitamin B12 1000 I1g intramuscularly were started. 3 months later the 0-carotene concentration (0-7 lunol/1) had improved and vitamin B12 (124 pmol/1) and folate (21-2 nmol/1) values were normal. Villous structure had improved too. Treatment with zidovudine was continued for a further 3 months at 600 mg per day. After 6 months of treatment with zidovudine repeat duodenal biopsies showed normal villous architecture with normal lamina propria cellularity. The diarrhoea had completely resolved. A repeat 14C-triolein breath test indicated a small improvement (I %). The serum 0 (0-3 )jmol/l) had again fallen, serum retinol was stable (1 -4 umol/1), and vitamin B12 (256 pmol/1) and folate (12-5 nmol/1) remained normal. His CD4 count was 780/ul and CD8 1320/ul. Direct infection of the gut mucosa by HIV has been confirmed" and structural changes in the small bowel are now recognised in HIV infection, independent of secondary infections.1,2,5,6 Furthermore malabsorption can occur early in HIV infection.2,s Improvement in bowel absorption and reversal of the HIVassociated structural changes in the bowel have not been previously
reported.
1087
This case shows that within 9 months of HI V seroconversion and lymphocyte count within the normal range, damage to the gastrointestinal mucosa can occur. Treatment with zidovudine produced significant improvement in small-bowel architecture, this being associated with a resolution of diarrhoea and improved biochemical indicators of malabsorption. at a CD4
MICHAEL HING CHRISTOPHER OLIVER REX MELVILLE
Albion Street Centre,
Sydney Hospital, Sydney, NSW 2010, Australia 1. Kotler DP, Gaetz HP, Lange M, Klein EB, Holt PR.
Enteropathy assodated with the
acquired immunodeficiency syndrome. Ann Intern Med 1984, 101: 421-28. 2 Ullrich R, Zeitz M, Heise W, L’age M, Hoffken G, Riecken EO. Small intestinal structure and function in patients infected with human immunodeficiency virus (HIV): evidence for HIV-induced enteropathy. Ann Intern Med 1988; 111: 15-21. 3. Nelson JA, Wiley CA, Reynolds-Kohler C, et al. Human immunodeficiency virus detected in bowel epithelium from patients with gastrointestinal symptoms. Lancet 1988; i: 259-62. 4
Mathijs JM, Hing MC, Grierson J, et al. HIV infection of rectal mucosa. Lancet 1988;
i: 1111. 5. Miller ARO, Griffin
6
GE, Batman P, et al. Jejunal mucosal architecture and fat absorption in male homosexuals infected with the human immunodeficiency virus. QJ Med 1988; 69: 1009-19. Greenson JK, Belitsos PC, Yardley JH, Bartlett JG. AIDS enteropathy: occult enteric infections and duodenal mucosal alterations m chronic diarrhoea. Ann Intern Med
1991; 114: 366-72.
DNA was extracted and digested with enzymes, followed by fractionation and Southern blotting onto ’Hybond-N’ (Amersham International). The membranes were hybridised overnight with a DNA probe that was labelled with 32P by a random labelling primed method. MCT112/microsatellite polymorphism was examined by polymerase chain reaction and products were electrophoresed on
6% polyacrilamide gel. As expected 14 children had a different haplotype to that of the affected sibling in at least one chromosome. A 7-year-old girl showed the same chromosome haplotypes as her 10-year-old affected sister (figure). At the time of the test this girl showed knee deep tendon hyporeflexia, suggesting the presence of Friedreich’s ataxia. Predictive diagnosis in Friedreich’s ataxia is a challenge for both physicians and parents since there is no specific treatment for this disease, and rehabilitation has not modified the natural history. Prediction of the development of the disease can be very stressful for patients and their parents. Thus we believe that predictive diagnosis should only be done when the physician needs to confirm clinical suspicion, as in our patient (11-2), or at the parents specific request. This work is
the Fondo de Investigación Sanitaria (FIS) and the Fundacion de Ataxias Hereditarias ’Adriana de Luz Caballer’. We thank the families for their cooperation, and Dr Y. Nakamura, Dr A. J. Driesel, and Dr J.-L. Mandel for gift of the MCT112, DR47, and 26P probes. grants
no
supported by
89/1932 and 91/0445
Genetic diagnosis of Friedreich’s ataxia b!R,—rnedreichataxia is inherited as an autosomal recessive trait. The Friedreich’s ataxia locus has been mapped to chromosome 9ql3-21’l, and all families with typical clinical features show genetic homogeneity.2 Two tightly linked marker loci, D9Sl5 (defined by probe MCT112) and D9S5 (defined by probes DR47 and 26P), have generated a linkage group within 1 -4 centimorgans (cM) of the Friedreich’s ataxia gene,3’ and Wallis et a15 made the first prenatal diagnosis, which can be offered to families with an accuracy of 99% or more.4,6 The disorder can also be diagnosed before symptoms develop. However, the poor long-term outlook and the lack of treatment for the disease raise several ethical issues about such studies. In a linkage disequilibrium study of Friedreich’s ataxia information about disease onset and evolution and genetic counselling about its autosomal recessive heredity pattern was provided for families. Seven families asked for predictive diagnosis of 15 seemingly healthy children aged under 15 years. Extended haplotypes were constructed with five DNA polymorphisms, three from D9S 15 locus and two from D9S5 locus. Four were restriction fragment-length polymorphisms (RFLPs) and one recognised a polymorphic microsatellite sequence7 (figure). 26P/Bst XI RFLP at D9S5, and the MCT112/microsatellite showed high polymorphism, with polymorphism information contents of 0-55 and 0-79, respectively. For RFLPs generating probe hybridisation,
Genetics Unit and Neurology Service, Hospital La Fe, Valencia 46009, Spain
FRANCISCO PALAU EUGENIA MONROS FELIX PRIETO JUAN J. VILCHEZ JOSE M. LOPEZ-ARLANDIS
1. Shaw J, Litcher P, Driesel AJ, Williamson R, Chamberlain S. Regional localisation of the Friedreich ataxia locus to human chromosome 9q13-q21·1. Cytogenet Cell
Genet 1990; 53: 221-24. 2. Chamberlain S, Shaw J, Wallis J, et al. Genetic homogeneity at the Friedreich’s ataxia locus on chromosome 9. Am J Hum Genet 1989; 44: 518-21. 3. Fujita R, Hanauer A, Sirugo G, Heilig R, Mandel JL. Additional polymorphisms at marker loci D9S5 and D9S15 generate extended haplotypes in linkage disequilibrium with Friedreich ataxia. Proc Natl Acad Sci USA 1990; 87: 1796-800. 4. Pandolfo M, Sirugo G, Antonelli A, et al. Friedreich ataxia in Italian families: genetic homogeneity and linkage disequilibrium with the marker loci D9S5 and D9S15. Am J Hum Genet 1990; 47: 228-35. 5. Wallis J, Shaw J, Wilkes D, et al. Prenatal diagnosis of Friedreich ataxia. Am J Med Genet 1989; 34: 458-61. 6. Hanauer A, Fujita R, Trouillas P, et al. Prenatal diagnosis of Friedreich ataxia. Lancet 1990; 335: 1102. 7. Wallis J, Williamson R, Chamberlain S. Identification of a hypervariable microsatellite polymorphism within D9S15 tightly linked to Friedreich’s ataxia. Hum Genet 1990; 85: 98-100.
Screening dyspepsia by serology to Helicobacter pylori in children SIR,-Dr Sobala and colleagues’ message (July 13, p 94) is very important in clinical practice. Young adults with dyspepsia who are seronegative for Helicobacter pylori and who are not NSAID users do not have peptic ulcer disease. We are evaluating a screening policy in children, and have shown that abnormal concentrations of IgG and/or IgA against H pylori identified infected children with 95% sensitivity and 84% specificity.l In addition, increased concentrations of specific antibodies were found in 6% of Italian children, irrespective of the presence of chronic dyspepsia. The infection seems to be unusual before 10 years of age, although seropositivity has been detected in children younger than this,l and infected infants have been described. We obtained serum samples prospectively from 46 children (age range 8-18 years) evaluated for recurrent epigastric pain. H pylorispecific IgG and IgA were measured by ELISA. 22 children were seropositive (8 were seropositive for IgG, 6 for IgA, and 8 for both IgG and IgA). 26 children (4 IgG seropositive, 6 IgA seropositive, 7 IgG and IgA seropositive, and 9 seronegative) were evaluated by upper gastrointestinal endoscopy with biopsy; 5 (4 IgG and 1 IgG and IgA seropositive) of the 22 seropositive children had refused some
Segregation
of
haplotypes
at Friedreich’s ataxia
region of
chromosome 9, showing identical pattern in subjects is-1 and 11-2.
Polymorphic
endoscopy. DNA markers
alleles on chromosomes
are
shown in the
same
order
as
numerical
The table shows diagnoses and H pylori status. All 11children with Hpylori-associated chronic gastritis had raised concentrations
ACETYLCHOLINESTERASE ACTIVITIES IN ADRENAL TISSUE OBTAINED AT NECROPSY FROM ALZHEIMER’S PATIENTS AND CONTROLS
Results are given as mean (SEM). *nmol acetylthiocholine hydrolysed per mm; U test
tp < 05, tpO 005,
Mann
Whitney
system, such as sympathetic ganglia, to see if they are similarly affected in AD. These results could have implications for the use of the peripheral nervous system as donor tissue for brain transplants aimed at restoring neuronal pathways destroyed by neurodegenerative disease. Autografts seem to have little chance of survival in patients with AD since the graft tissue itself may be affected by the disease. Investigations in animals have demonstrated that AChE is secreted from the adrenal medulla.2 Reduced levels of soluble AChE in the adrenal gland in AD could therefore result in reduced secretion of AChE from the gland into the blood. However, there have been reports that plasma AChE activities are increased in patients with AD.4 Secretion of AChE from forebrain regions also seems to be abnormal in AD, leading to lower levels in ventricular cerebrospinal fluid.6 Hence AD may be associated with a defect in the secretion of AChE. The physiological significance of altered AChE secretion is at present unclear, especially in the peripheral nervous system, but there is evidence that AChE may have a neuromodulatory role in the central nervous system.7
transketolase were measured in erythrocyte haemolysates without and with an excess thiamine pyrophosphate (TPP).5 The % activation (TPP effect) is an index of thiamine status. In our laboratory, as elsewhere, TPP effect values above 15% indicate moderate-to-severe thaimine deficiency. 9 patients (23%) were thiamine deficient on this criterion, and 8 of these 9 were receiving zidovudine. Wernicke’s encephalopathy can be prevented if thiamine supplementation is given early enough in the course of the disease. The four reports of Wernicke’s encephalopathy in AIDS patients were post-mortem findings; neurological symptoms indicative of Wernicke’s encephalopathy had not been apparent before death and thiamine supplements had not been administered. Our results suggest that substantial numbers of patients with AIDS or AIDS-related complex are thiamine deficient and at risk of Wernicke’s encephalopathy. Thiamine supplementation in HIVpositive patients might be helpful. Laboratory of Neurochemistry, Centre de Recherche André-Viallet,
Microbiology Service, and Haematology Service, Hôpital Saint-Luc, Montreal, Quebec H2X 3J4, Canada
Davtyan DG, Vinters HV. Wemicke’s encephalopathy in AIDS patient treated with zidovudine. Lancet 1987; i: 919-20. 2. Foresti V, Confalonieri F. Wernicke’s encephalopathy in AIDS. Lancet 1987; i: 1499. 3. Lindboe CF, Loberg EM. Wernicke’s encephalopathy in non-alcoholics: an autopsy study. J Neurol Sci 1989; 90: 125-29. 4. Schwenk J, Gosztonyl G, Thieranf P, Iglesias J, Langer E. Wernicke’s encephalopathy in two patients with acquired immunodeficiency syndrome. J Neurol 1990; 7: 445-47. 5. Butterworth RF. Thiamine malnutrition and brain development. In: Current topics in nutrition and disease, vol XVI. New York. Alan R. Liss, 1987: 287-304. 1.
Department of Physiology, Royal Free Hospital School of Medicine, Department of Neuropathology, Radcliffe Infirmary,
BRENDAN MCDONALD
Oxford
1. Averback P. Two new lesions in Alzheimer’s disease. Lancet
2. 3.
1983; ii. 1203.
Somogyi P, Chubb IW, Smith AD. A possible structural basis for the extracellular release of acetylcholinesterase. Proc R Soc B 1975; 191: 271-83. Smith AD, Cuello AC. Alzheimer’s disease and acetylcholinesterase-containing
Lancet 1984; i: 513. Z. Cholinesterase and its molecular forms in pathological states. Progr Neurobiol 1988; 31: 311-30. 5. Appleyard ME, McDonald B, Benjamin L Presence of a soluble form of acetylcholinesterase m human ocular fluids. Br J Ophthalmol 1991; 75: 276-79. 6. Appleyard ME, Smith AD, Berman P, et al. Cholinesterase activities in cerebrospinal fluid of patients with senile dementia of the Alzheimer type. Brain 1987; 110: 1309-22. 7. Appleyard ME, Jahnsen H. Non-cholinergic effect of acetylcholinesterase upon the membrane properties of mammalian cerebellar Purkinje cells. Eur J Neurosci 1989; neurons.
4.
Rakonczay
(suppl 2): 129.
Thiamine
Zidovudine for HIV enteropathy
MARGARET E. APPLEYARD
London NW3 2PF, UK
deficiency in AIDS
SIR,-Four recent independent reports have described neuropathological changes (mammillary body atrophy, perivascular haemorrhagic lesions) characteristic of Wernicke’s encephalopathy in patients with AIDS.1 No patient was alcoholic and a diagnosis of Wernicke’s encephalopathy had not been entertained before death. Wernicke’s encephalopathy results from thiamine deficiency, generally
consequence of chronic other conditions associated with grossly impaired nutrition. Severe nutritional deficiencies are common in AIDS. These findings prompted us to evaluate thiamine status in patients with AIDS. 39 patients (36 male, 3 female; aged 22-67) with AIDS or AIDS-related complex were studied at various stages of the disease. In no case was there a history of alcohol abuse, nor were there any neurological symptoms (ophthalmoplegia, ataxia) suggestive of Wernicke’s encephalopathy. None was taking thiamine supplements. Thiamine status was measured by transketolase activation assay. Activities of the thiamine-dependent enzyme as
a
alcoholism, gastrointestinal disease,
or
ROGER F. BUTTERWORTH CHRISTIANE GAUDREAU JEAN VINCELETTE ANNE-MARIE BOURGAULT FRANÇOIS LAMOTHE ANNE-MARIE NUTINI
SIR,-A 22-year-old homosexual man was enrolled in a prospective study of nutrition in HIV infection. 3 months earlier he had seroconverted in association with primary HIV illness. Since then he had been well, except for occasional mild diarrhoea. His CD4 count was 651/)il and the CD8 count was 1260/ul. He was HIV p24 antigen negative but with a (32 microblobulin of 3-5 mg/1 A biochemical screen indicated possible (normal 0-2), serum retinol 1 ’3 Ilffiol/l (1 4-40), vitamin B12 44 pmol/1 (110-700), folate 6-8 nmol/1 (6-8-38-5), and ferritin 45 pmol/1 (55-880). The peripheral blood film and haemoglobin were normal. Proximal gut function was tested by the 14C-triolein breath test and shown to be abnormal (triolein exhaled per hour as 14C02 was 0’ 1 %, normal > 2-6%). Endoscopy and biopsy of the distal second part of the duodenum indicated partial villous atrophy with mildly increased intraepithelial lymphocytes and diffuse moderate-grade chronic inflammatory infiltrate in the lamina propria. These results are consistent with HIV enteropathy.l,2 Zidovudine 400 mg daily and monthly vitamin B12 1000 I1g intramuscularly were started. 3 months later the 0-carotene concentration (0-7 lunol/1) had improved and vitamin B12 (124 pmol/1) and folate (21-2 nmol/1) values were normal. Villous structure had improved too. Treatment with zidovudine was continued for a further 3 months at 600 mg per day. After 6 months of treatment with zidovudine repeat duodenal biopsies showed normal villous architecture with normal lamina propria cellularity. The diarrhoea had completely resolved. A repeat 14C-triolein breath test indicated a small improvement (I %). The serum 0 (0-3 )jmol/l) had again fallen, serum retinol was stable (1 -4 umol/1), and vitamin B12 (256 pmol/1) and folate (12-5 nmol/1) remained normal. His CD4 count was 780/ul and CD8 1320/ul. Direct infection of the gut mucosa by HIV has been confirmed" and structural changes in the small bowel are now recognised in HIV infection, independent of secondary infections.1,2,5,6 Furthermore malabsorption can occur early in HIV infection.2,s Improvement in bowel absorption and reversal of the HIVassociated structural changes in the bowel have not been previously
reported.
1087
This case shows that within 9 months of HI V seroconversion and lymphocyte count within the normal range, damage to the gastrointestinal mucosa can occur. Treatment with zidovudine produced significant improvement in small-bowel architecture, this being associated with a resolution of diarrhoea and improved biochemical indicators of malabsorption. at a CD4
MICHAEL HING CHRISTOPHER OLIVER REX MELVILLE
Albion Street Centre,
Sydney Hospital, Sydney, NSW 2010, Australia 1. Kotler DP, Gaetz HP, Lange M, Klein EB, Holt PR.
Enteropathy assodated with the
acquired immunodeficiency syndrome. Ann Intern Med 1984, 101: 421-28. 2 Ullrich R, Zeitz M, Heise W, L’age M, Hoffken G, Riecken EO. Small intestinal structure and function in patients infected with human immunodeficiency virus (HIV): evidence for HIV-induced enteropathy. Ann Intern Med 1988; 111: 15-21. 3. Nelson JA, Wiley CA, Reynolds-Kohler C, et al. Human immunodeficiency virus detected in bowel epithelium from patients with gastrointestinal symptoms. Lancet 1988; i: 259-62. 4
Mathijs JM, Hing MC, Grierson J, et al. HIV infection of rectal mucosa. Lancet 1988;
i: 1111. 5. Miller ARO, Griffin
6
GE, Batman P, et al. Jejunal mucosal architecture and fat absorption in male homosexuals infected with the human immunodeficiency virus. QJ Med 1988; 69: 1009-19. Greenson JK, Belitsos PC, Yardley JH, Bartlett JG. AIDS enteropathy: occult enteric infections and duodenal mucosal alterations m chronic diarrhoea. Ann Intern Med
1991; 114: 366-72.
DNA was extracted and digested with enzymes, followed by fractionation and Southern blotting onto ’Hybond-N’ (Amersham International). The membranes were hybridised overnight with a DNA probe that was labelled with 32P by a random labelling primed method. MCT112/microsatellite polymorphism was examined by polymerase chain reaction and products were electrophoresed on
6% polyacrilamide gel. As expected 14 children had a different haplotype to that of the affected sibling in at least one chromosome. A 7-year-old girl showed the same chromosome haplotypes as her 10-year-old affected sister (figure). At the time of the test this girl showed knee deep tendon hyporeflexia, suggesting the presence of Friedreich’s ataxia. Predictive diagnosis in Friedreich’s ataxia is a challenge for both physicians and parents since there is no specific treatment for this disease, and rehabilitation has not modified the natural history. Prediction of the development of the disease can be very stressful for patients and their parents. Thus we believe that predictive diagnosis should only be done when the physician needs to confirm clinical suspicion, as in our patient (11-2), or at the parents specific request. This work is
the Fondo de Investigación Sanitaria (FIS) and the Fundacion de Ataxias Hereditarias ’Adriana de Luz Caballer’. We thank the families for their cooperation, and Dr Y. Nakamura, Dr A. J. Driesel, and Dr J.-L. Mandel for gift of the MCT112, DR47, and 26P probes. grants
no
supported by
89/1932 and 91/0445
Genetic diagnosis of Friedreich’s ataxia b!R,—rnedreichataxia is inherited as an autosomal recessive trait. The Friedreich’s ataxia locus has been mapped to chromosome 9ql3-21’l, and all families with typical clinical features show genetic homogeneity.2 Two tightly linked marker loci, D9Sl5 (defined by probe MCT112) and D9S5 (defined by probes DR47 and 26P), have generated a linkage group within 1 -4 centimorgans (cM) of the Friedreich’s ataxia gene,3’ and Wallis et a15 made the first prenatal diagnosis, which can be offered to families with an accuracy of 99% or more.4,6 The disorder can also be diagnosed before symptoms develop. However, the poor long-term outlook and the lack of treatment for the disease raise several ethical issues about such studies. In a linkage disequilibrium study of Friedreich’s ataxia information about disease onset and evolution and genetic counselling about its autosomal recessive heredity pattern was provided for families. Seven families asked for predictive diagnosis of 15 seemingly healthy children aged under 15 years. Extended haplotypes were constructed with five DNA polymorphisms, three from D9S 15 locus and two from D9S5 locus. Four were restriction fragment-length polymorphisms (RFLPs) and one recognised a polymorphic microsatellite sequence7 (figure). 26P/Bst XI RFLP at D9S5, and the MCT112/microsatellite showed high polymorphism, with polymorphism information contents of 0-55 and 0-79, respectively. For RFLPs generating probe hybridisation,
Genetics Unit and Neurology Service, Hospital La Fe, Valencia 46009, Spain
FRANCISCO PALAU EUGENIA MONROS FELIX PRIETO JUAN J. VILCHEZ JOSE M. LOPEZ-ARLANDIS
1. Shaw J, Litcher P, Driesel AJ, Williamson R, Chamberlain S. Regional localisation of the Friedreich ataxia locus to human chromosome 9q13-q21·1. Cytogenet Cell
Genet 1990; 53: 221-24. 2. Chamberlain S, Shaw J, Wallis J, et al. Genetic homogeneity at the Friedreich’s ataxia locus on chromosome 9. Am J Hum Genet 1989; 44: 518-21. 3. Fujita R, Hanauer A, Sirugo G, Heilig R, Mandel JL. Additional polymorphisms at marker loci D9S5 and D9S15 generate extended haplotypes in linkage disequilibrium with Friedreich ataxia. Proc Natl Acad Sci USA 1990; 87: 1796-800. 4. Pandolfo M, Sirugo G, Antonelli A, et al. Friedreich ataxia in Italian families: genetic homogeneity and linkage disequilibrium with the marker loci D9S5 and D9S15. Am J Hum Genet 1990; 47: 228-35. 5. Wallis J, Shaw J, Wilkes D, et al. Prenatal diagnosis of Friedreich ataxia. Am J Med Genet 1989; 34: 458-61. 6. Hanauer A, Fujita R, Trouillas P, et al. Prenatal diagnosis of Friedreich ataxia. Lancet 1990; 335: 1102. 7. Wallis J, Williamson R, Chamberlain S. Identification of a hypervariable microsatellite polymorphism within D9S15 tightly linked to Friedreich’s ataxia. Hum Genet 1990; 85: 98-100.
Screening dyspepsia by serology to Helicobacter pylori in children SIR,-Dr Sobala and colleagues’ message (July 13, p 94) is very important in clinical practice. Young adults with dyspepsia who are seronegative for Helicobacter pylori and who are not NSAID users do not have peptic ulcer disease. We are evaluating a screening policy in children, and have shown that abnormal concentrations of IgG and/or IgA against H pylori identified infected children with 95% sensitivity and 84% specificity.l In addition, increased concentrations of specific antibodies were found in 6% of Italian children, irrespective of the presence of chronic dyspepsia. The infection seems to be unusual before 10 years of age, although seropositivity has been detected in children younger than this,l and infected infants have been described. We obtained serum samples prospectively from 46 children (age range 8-18 years) evaluated for recurrent epigastric pain. H pylorispecific IgG and IgA were measured by ELISA. 22 children were seropositive (8 were seropositive for IgG, 6 for IgA, and 8 for both IgG and IgA). 26 children (4 IgG seropositive, 6 IgA seropositive, 7 IgG and IgA seropositive, and 9 seronegative) were evaluated by upper gastrointestinal endoscopy with biopsy; 5 (4 IgG and 1 IgG and IgA seropositive) of the 22 seropositive children had refused some
Segregation
of
haplotypes
at Friedreich’s ataxia
region of
chromosome 9, showing identical pattern in subjects is-1 and 11-2.
Polymorphic
endoscopy. DNA markers
alleles on chromosomes
are
shown in the
same
order
as
numerical
The table shows diagnoses and H pylori status. All 11children with Hpylori-associated chronic gastritis had raised concentrations
