629
463—also results in the loss of an MspI site. This arginine-tocysteine mutation has been identified in both type 1 and type 3 Gaucher disease and was present in 11of 62 patients.’ If the 463 mutation were present Dahl and colleagues’ 598 bp segment of DNA would not be cleaved to 580 bp, and this subtle difference might not be appreciated on a 1-2% gel. (Incidentally, the bands in the illustration provided by Dahl et al seem to be mislabelled in respect of size.) Investigators screening for gene mutations in Gaucher’s disease should be aware of the 463 mutation. If Msp is used for screening, the laboratory should amplify a larger DNA segment, so that the presence and/or absence of both the 444 and 463 mutations can be established simultaneously. Use of the technique described by Dahl et al may lead to errors in genetic counselling when applied to a population other than the Norrbottnian Gaucher patients. Clinical Neuroscience Branch, Section of Molecular Neurogenetics, National Institute of Mental Health, Bethesda, Maryland 20892, USA
ELLEN SIDRANSKY KARA MAYSAK EDWARD I. GINNS
1 Tsuji S, Choudary PW, Martin BM, et al. A mutation in the human glucocerebrosidase gene in neuronopathic Gaucher’s disease. N Engl J Med 1987; 316: 570-75. 2. Martin BM, Sidransky E, Ginns EI. Gaucher disease: advances and challenges. Adv Pediatr 1989; 36: 277-306. 3 Hong CM, Oshashi T, Yu YJ, Weiler S, Barranger JA Sequence of two alleles responsible for Gaucher’s disease. DNA Cell Biol 1990; 9: 232-41 4. Sidransky E, Tsuji S, Stubblefield B, Martin BM, Ginns EI Current genotypic analysis does not adequately account for phenotypic variation in Gaucher patients. Vth International Congress of Inborn Errors of Metabolism; OC4 7 (abstr).
Genetic markers of familial coronary heart disease SIR,-We have reported’ that in 713 men aged 30-59 a history of coronary heart disease (CHD) before age 60 in first-degree relatives
is associated with a significantly increased frequency of CHD morbidity in those who have DNA restriction fragment length polymorphism (RLFP) markers of the apolipoprotein AI/CIII/ AIV gene cluster. The RLFP are the minor alleles (X2, M2, Pz, Sz) of four biallelic markers identified with the enzymes XmnI, MspI, PstI, and SacI, respectively. We have now examined these men for allele status at a fifth RLFP in this gene region. This region identified by PvulI is in the first intron of the Apo CIII gene. DNA stored at - 20°C was digested with PvuII and DNA fragments were separated by electrophoresis and transferred to nitrocellulose filters after denaturation. The filters were then hybridised with a labelled CIII cDNA probe (pAT/CIII/8, kindly provided by Dr C. C. Shoulders). This probe identifies a constant fragment 1 ’4 kb in length and variable fragments of 1 kb (major allele, VI) and 0,87 kb (minor allele, Vz), the allele frequencies being 0-763 and 0’237, respectively. An increased frequency of V, has been reported in patients with angiographically proven CHDIn our study Vz frequency was not increased in men with CHD; the relative CHD frequency is significantly higher in men homozygous for Vl, although only in those who have one or more of the minor alleles, Xz
M2, P2, S2 (p < 0001). The five markers
are no more
than 10 kb bases apart. Of 32 11(a-k, table). Men with
possible haplotypes we are able to identify
APO Al/Clll/AIV MARKER HAPLOTYPES
haplotypes c-h have a higher relative premature CHD frequency of 2-00 (n 278; p < 0-001). The relative frequency is higher when 2 or more first-degree relatives are affected but the numbers are small and the difference is not significant. In a logistic regression analysis neither family history on its own nor haplotypes c-h emerges as a significant co-variable of CHD morbidity, but when the two are combined the odds ratio is 2 92 (95% confidence limits 1’91-3-91; p=0016). If the variables age, social class, smoking habits, blood pressure, plasma levels of cholesterol, apolipoproteins AI and B, triglycerides, and total cholesterol/HDL cholesterol ratios are included in the analysis, the co-variate adjusted odds ratio for CHD morbidity and haplotypes c-h in men with a family history of premature CHD is 2-73 (1 72-3 73; p 0023). The higher prevalence of premature familial CHD morbidity in those with haplotypes c to h is therefore independent of other major CHD risk factors. The selective association of some marker haplotypes in the region of the AI/CIII/AIV genes with significantly higher frequencies of familial CHD morbidity supports the conclusion that liability to CHD is enhanced by variants of one or more of these genes or of their regulators. =
=
MRC Human Genetics Unit, University Department of Medicine and Department of Clinical Chemistry, Western General Hospital, Edinburgh EH4 2XU, UK
W. H. PRICE S. W. MORRIS A. H. KITCHIN P. R. WENHAM P. R. S. MCKENZIE P. M. DONALD
1. Price WH, Morris SW, Kitchin AH, Wenham PR, Burgon PRS, Donald PM. DNA restriction fragment length polymorphisms as markers of familial coronary heart disease Lancet 1989; i: 1407-11. 2. Coleman RT, Gonzalez PA, Funke H, Assmann G, Levy-Wilson B, Frossard PM. Polymorphisms in the apolipoprotein AI-CIII gene complex. Mol Biol Med 1986; 3: 213-28. 3. Frossard PM, Funke H, Coleman RT, Assmann G. Genetic markers for coronary atherosclerosis in the human apolipoprotein AI-CIII-AIV gene complex. Am J Hum Gener 1986; 39: A199.
Secondary metabolic defects in spinal muscular atrophy type II SiR,—The genetic mapping of chronic childhood-onset spinal muscular atrophy types II (intermediate) and III (KugelbergWelander disease) and of acute SMA (type I, Werdnig-Hoffmann disease) allows prenatal diagnosis in informative families (Dr Melki and colleagues, Aug 4, p 271). However, this advance does not provide the early prospect of any specific therapy for children with these diseases. Any palliative treatment should be considered. We here report metabolic studies in 14 children (6 boys, 8 girls) with SMA type 11.1 Muscle biopsy findings were typical of SMA type II. In one biopsy sample there was a mild and in another a clear increase in the lipid content of type I fibres. Every patient had a typical electromyographic neurogenic pattern. By age at metabolic study the patients could be divided into three groups: Group 1, aged 1-3 years (n=5; age at onset, birth [1 floppy infant] to 18 months). 3 children could not maintain a sitting position; 1 could not stand up when supported, and 1 could. Group 2, aged J- 5 years (n=5, age at onset, 6-18 months). These children had acquired, with a delay, a very unsteady gait. Children with SMA type II are never able to walk.’ Nonetheless the early onset and the muscle biopsy findings were typical of SMA type II. This group may represent borderline cases between SMA type II and type 111.1 Group 3, aged C-/ 7 5 years (n = 4; age at onset, 9-18 months). These children were wheelchair-bound, and had some respiratory
problems. of organic acids in abnormal excretion of ethylmalonic acid in all 14 children, of methylsuccinic acid in 9, of glutaric acid in 8, and of adipic acid in 7. High-pressure liquid chromatography of urinary acylcarnitines was done in 8 patients. All 8 had a high excretion of isobutyryl, 3 of n-butyryl,1 of2-methylbutyryl,1 of isovaleryl, and 2 of acetyl carnitine. There was a carnitine deficiency in serum in 10
Gas-chromatography/mass-spectrometry
urine showed
Mspl,Sacl,Xmnl,Pstl, and Pvull refer to restriction endonucleases used (1 = major allele, 2= minor allele)
an
630
of 14
and in muscle in 6 out of 10 children. Muscle decreased in the 2 patients studied. Ql0 These urinary organic acid and acylcamitine profiles point to a multiple FAD-linked acyl-CoA dehydrogenase deficiency,2 predominating in the fatty acid &bgr;-oxidation pathway but also involving the" branched-chain aminoacid and lysine oxidation pathways. This apparent acyl-CoA dehydrogenase deficiency and the muscle carnitine deficiency in patients with SMA type II are probably secondary to denervation, as has been demonstrated in animal experiments.34 Carnitine deficiency may be due, partly, to intramitochondrial accumulation of acylcarnitines, followed by renal excretion.s The reduced availability of acetyl-CoA could aggravate already impaired muscle function in SMA type II. Treatment aimed at stimulating acyl-CoA dehydrogenase activity (riboflavin [an FAD precursor], coenzyme Qlo, Lcarnitine, and a low-fat/high-carbohydrate diet) has been given to 13 children for between 3 and 30 months (mean 16). In group 1, the 2 youngest children can now maintain a sitting position, 1 (the floppy infant) can stand up with support, 1 has been walking unaided since the age of 28 months, and the oldest patient, treated for only 3 months, has more hand skill. In group 2, 4 patients can now walk 700 m to 3-4 km. (One patient, who died of a Reye’s-like syndrome at age 6 years, was not treated.) In group 3, there was no improvement in the oldest child (11-5 years); 1 child, now aged 9-5 years, can walk unaided for 20 m. In the 2 others, progress has been impaired by contractures of hips and knees; however, their arms are stronger. In 2 patients forced vital capacity has improved. These first results are encouraging; however, we are well aware of the possibility of spontaneous improvement in such patients. Further studies are needed to assess the frequency of secondary metabolic defects among patients with SMA type II and to monitor long term the proposed treatment. Infants with SMA type I should also be screened for metabolic defects.6 Children with type III are less likely to exhibit the same metabolic profile because of the intense reinnervation process.4 out
patients,
coenzyme
was
Metabolic Unit, Paediatric Clinic, Hôpital de la Salpêtrière, 75651 Paris, France
incidence of 38-3 per 100 000 in the general population, based on a survey conducted in Ilorin, in 1988. Our estimated permanent disability secondary to dracunculiasis was based on an estimated 1988 population of 481 000 (projected from 1963 census). The total number of cases of guineaworm disease revealed in a 1988 village-by-village survey in Ilorin was 4568/ to give an annual incidence of 950 per 100 000. The survey was of good quality but even so some cases may have been missed. Muller3estimates the load of permanent disability resulting from guineaworm disease at 0.5% of cases per year, giving an estimated annual permanent disability rate of 5 per 100 000 population (0-005 x 950) in Ilorin in 1988. However, a recent study from Sokoto State reported dracunculiasis-related permanent crippling to be as high as 0-9% in that part of Nigeria.’ Even with the lower disability rate permanent disability from guineaworm disease in Ilorin in 1988 was 13% of that resulting from poliomyelitis, and cumulative permanent disability over 20 years would be at least 100 per 100 000, compared with 750 per 100 000 population over the same period for poliomyelitis. Estimates of the annual incidence in Africa range from 3320 0005 to 10 million6 cases. According to these estimates and Muller’s figure between 16 600 and 50 000 Africans are permanently crippled as a result of guineaworm every year. This disease, unlike poliomyelitis, is limited to seventeen countries in Africa. Poliomyelitis is estimated to lead to permanent disability in 168 000 children in Africa every year7 The variation in case incidence and permanent disability rates for guineaworm disease point to the need for well-designed surveys to defme the extent of permanent disability from this preventable disease. Improved case counting should also help provide a more accurate estimate of permanent disability. With the much more prevalent temporary disability caused by guineaworm disease this permanent disability is a considerable burden on endemic rural communities.8 Aggressive early efforts are needed by all countries with endemic dracunculiasis to conduct national searches for dracunculiasis and initiate eradication programmes. Global 2000 Inc, Carter Presidential Center, Atlanta, Georgia 30307, USA
JEAN-PAUL HARPEY
INSERM U75,
CHU-Necker, Paris
CHRISTIANE CHARPENTIER
INSERM U134, Hôpital de la Salpêtrière
Division of Parasitic Diseases, Center for Infectious Diseases, Centres for Disease Control,
MARION PATURNEAU-JOUAS
Atlanta, Georgia
R. IMTIAZ D. R. HOPKINS
E. RUIZ-TIBEN
Laboratory of
Neurophysiology, Hôpital Trousseau, Paris
FRANCIS RENAULT
INSERM U153, Paris
NORMA ROMERO MICHEL FARDEAU
1. Dubovitz V. Muscle disorders m childhood. London: WB Saunders, 1978: 146-90. 2. Frerman FE, Goodman SI. Glutanc acidemia type II and defects of the mitochondrial respiratory chain. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds The metabolic basis of inherited disease. New York: McGraw Hill, 1989: 915-31. 3. Jato-Rodriguez J, Liang C-R, Lin CH, Hudson AJ, Strickland KP. Companson of the intermediary metabolism of fatty acids in denervated and dystrophic munne skeletal muscle. J Neurol Neurosurg Psychiatry 1975; 38: 1083-89. 4. Bresolin N, Freddo L, Tegazzin V, Bet L, Armani M, Angelini C. Carnitine and acyltransferase in experimental neurogenic atrophies: changes with treatment J Neurol 1984; 231: 170-75. 5. Roe CR, Coates PM. Acyl-CoA dehydrogenase deficiencies. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease. New York: McGraw Hill, 1989. 889-914. 6. Kelley RI, Sladky JT. Dicarboxylic aciduria in an infant with spinal muscular atrophy. Ann Neurol 1986; 20: 734-36.
1 Parakoyi B, Babaniyi O. Incidence of neonatal tetanus and polio m Ilorin LGA, Kwara State, Nigena 1988. Epidemiol Bull WHO/AFRO 1989, 5: 15 2. Anon. Dracunculiasis: Nigeria. Wkly Epidemiol Rec 1989; 64: 207-10. 3 Muller R. Guinea worm disease: epidemiology, control, and treatment. Bull WHO 1979; 57: 683-89 4. Kabiru, Abdullahi. Guinea worm infection: a case study of Kiri-manai villae in Gwadabawa local government area of Sokoto State, Nigeria. Ibadan: Ibadan University Press, 1988: 38. 5. Watts SJ. Dracunculiasis in Africa in 1986: its geographic extent, incidence, and at-risk population. Am J Trop Med Hyg 1987; 37: 119-25 6. Duke BO. Filariasis. WHO informal report/TDR 1976. Geneva: WHO, 1976. 7 Foster SO, Kesseng-Maben G, N’jie H, Coffi E. Control of poliomyelitis in Africa. Rev Infect Dis 1984; 6 (suppl 2): S433-37. 8. Smith GS, Blum D, Huttly SRA, Okeke N, et al. Disability from dracunculiasis: effect on mobility. Ann Trop Med Parasitol 1989; 83: 151-58
Diagnostic value of free subunits of serum gonadotropin in testicular cancer
chorionic
SIR,-The importance of human chorionic gonadotropin (hCG) as
Permanent
disability from dracunculiasis
SIR,-Several studies have reported on the prevalence of but permanent disability resulting from poliomyelitis’ dracunculiasis (guineaworm disease), another preventable cause of permanent disability, has not received the same attention. We have compared estimates of the permanent disability associated with poliomyelitis and that associated with guineaworm disease in the Ilorin local government area, Kwara State, Nigeria. Parakoyi and Babaniyil reported a prevalence rate for
poliomyelitis
lameness of 8-4 per 1000
population
and
an
annual
marker for testicular cancer has long been recognised.’ diagnostic and prognostic value of serum free &bgr;-subunit (hCG&bgr;) and especially of free a-subunit (hCGa), which is common to all human glycoprotein hormones, is still debated.2-4 We have developed highly sensitive and specific immunoenzymometric assays (IEMA) for free hCGcx, free hCG&bgr;, and holo-hCG with a panel of monoclonal antibodies produced in our laboratory.’ The established two-site IEMAs for the quantification of hCGx,
a tumour
The
hCG&bgr;, and holo-hCG showed sensitivities of between 8 and 10 pg/ml. The crossreactivities with holo-hCG in the IEMAs for the free ot-subunit and &bgr;-subunit were less than 0-1% and 0’01%,
463—also results in the loss of an MspI site. This arginine-tocysteine mutation has been identified in both type 1 and type 3 Gaucher disease and was present in 11of 62 patients.’ If the 463 mutation were present Dahl and colleagues’ 598 bp segment of DNA would not be cleaved to 580 bp, and this subtle difference might not be appreciated on a 1-2% gel. (Incidentally, the bands in the illustration provided by Dahl et al seem to be mislabelled in respect of size.) Investigators screening for gene mutations in Gaucher’s disease should be aware of the 463 mutation. If Msp is used for screening, the laboratory should amplify a larger DNA segment, so that the presence and/or absence of both the 444 and 463 mutations can be established simultaneously. Use of the technique described by Dahl et al may lead to errors in genetic counselling when applied to a population other than the Norrbottnian Gaucher patients. Clinical Neuroscience Branch, Section of Molecular Neurogenetics, National Institute of Mental Health, Bethesda, Maryland 20892, USA
ELLEN SIDRANSKY KARA MAYSAK EDWARD I. GINNS
1 Tsuji S, Choudary PW, Martin BM, et al. A mutation in the human glucocerebrosidase gene in neuronopathic Gaucher’s disease. N Engl J Med 1987; 316: 570-75. 2. Martin BM, Sidransky E, Ginns EI. Gaucher disease: advances and challenges. Adv Pediatr 1989; 36: 277-306. 3 Hong CM, Oshashi T, Yu YJ, Weiler S, Barranger JA Sequence of two alleles responsible for Gaucher’s disease. DNA Cell Biol 1990; 9: 232-41 4. Sidransky E, Tsuji S, Stubblefield B, Martin BM, Ginns EI Current genotypic analysis does not adequately account for phenotypic variation in Gaucher patients. Vth International Congress of Inborn Errors of Metabolism; OC4 7 (abstr).
Genetic markers of familial coronary heart disease SIR,-We have reported’ that in 713 men aged 30-59 a history of coronary heart disease (CHD) before age 60 in first-degree relatives
is associated with a significantly increased frequency of CHD morbidity in those who have DNA restriction fragment length polymorphism (RLFP) markers of the apolipoprotein AI/CIII/ AIV gene cluster. The RLFP are the minor alleles (X2, M2, Pz, Sz) of four biallelic markers identified with the enzymes XmnI, MspI, PstI, and SacI, respectively. We have now examined these men for allele status at a fifth RLFP in this gene region. This region identified by PvulI is in the first intron of the Apo CIII gene. DNA stored at - 20°C was digested with PvuII and DNA fragments were separated by electrophoresis and transferred to nitrocellulose filters after denaturation. The filters were then hybridised with a labelled CIII cDNA probe (pAT/CIII/8, kindly provided by Dr C. C. Shoulders). This probe identifies a constant fragment 1 ’4 kb in length and variable fragments of 1 kb (major allele, VI) and 0,87 kb (minor allele, Vz), the allele frequencies being 0-763 and 0’237, respectively. An increased frequency of V, has been reported in patients with angiographically proven CHDIn our study Vz frequency was not increased in men with CHD; the relative CHD frequency is significantly higher in men homozygous for Vl, although only in those who have one or more of the minor alleles, Xz
M2, P2, S2 (p < 0001). The five markers
are no more
than 10 kb bases apart. Of 32 11(a-k, table). Men with
possible haplotypes we are able to identify
APO Al/Clll/AIV MARKER HAPLOTYPES
haplotypes c-h have a higher relative premature CHD frequency of 2-00 (n 278; p < 0-001). The relative frequency is higher when 2 or more first-degree relatives are affected but the numbers are small and the difference is not significant. In a logistic regression analysis neither family history on its own nor haplotypes c-h emerges as a significant co-variable of CHD morbidity, but when the two are combined the odds ratio is 2 92 (95% confidence limits 1’91-3-91; p=0016). If the variables age, social class, smoking habits, blood pressure, plasma levels of cholesterol, apolipoproteins AI and B, triglycerides, and total cholesterol/HDL cholesterol ratios are included in the analysis, the co-variate adjusted odds ratio for CHD morbidity and haplotypes c-h in men with a family history of premature CHD is 2-73 (1 72-3 73; p 0023). The higher prevalence of premature familial CHD morbidity in those with haplotypes c to h is therefore independent of other major CHD risk factors. The selective association of some marker haplotypes in the region of the AI/CIII/AIV genes with significantly higher frequencies of familial CHD morbidity supports the conclusion that liability to CHD is enhanced by variants of one or more of these genes or of their regulators. =
=
MRC Human Genetics Unit, University Department of Medicine and Department of Clinical Chemistry, Western General Hospital, Edinburgh EH4 2XU, UK
W. H. PRICE S. W. MORRIS A. H. KITCHIN P. R. WENHAM P. R. S. MCKENZIE P. M. DONALD
1. Price WH, Morris SW, Kitchin AH, Wenham PR, Burgon PRS, Donald PM. DNA restriction fragment length polymorphisms as markers of familial coronary heart disease Lancet 1989; i: 1407-11. 2. Coleman RT, Gonzalez PA, Funke H, Assmann G, Levy-Wilson B, Frossard PM. Polymorphisms in the apolipoprotein AI-CIII gene complex. Mol Biol Med 1986; 3: 213-28. 3. Frossard PM, Funke H, Coleman RT, Assmann G. Genetic markers for coronary atherosclerosis in the human apolipoprotein AI-CIII-AIV gene complex. Am J Hum Gener 1986; 39: A199.
Secondary metabolic defects in spinal muscular atrophy type II SiR,—The genetic mapping of chronic childhood-onset spinal muscular atrophy types II (intermediate) and III (KugelbergWelander disease) and of acute SMA (type I, Werdnig-Hoffmann disease) allows prenatal diagnosis in informative families (Dr Melki and colleagues, Aug 4, p 271). However, this advance does not provide the early prospect of any specific therapy for children with these diseases. Any palliative treatment should be considered. We here report metabolic studies in 14 children (6 boys, 8 girls) with SMA type 11.1 Muscle biopsy findings were typical of SMA type II. In one biopsy sample there was a mild and in another a clear increase in the lipid content of type I fibres. Every patient had a typical electromyographic neurogenic pattern. By age at metabolic study the patients could be divided into three groups: Group 1, aged 1-3 years (n=5; age at onset, birth [1 floppy infant] to 18 months). 3 children could not maintain a sitting position; 1 could not stand up when supported, and 1 could. Group 2, aged J- 5 years (n=5, age at onset, 6-18 months). These children had acquired, with a delay, a very unsteady gait. Children with SMA type II are never able to walk.’ Nonetheless the early onset and the muscle biopsy findings were typical of SMA type II. This group may represent borderline cases between SMA type II and type 111.1 Group 3, aged C-/ 7 5 years (n = 4; age at onset, 9-18 months). These children were wheelchair-bound, and had some respiratory
problems. of organic acids in abnormal excretion of ethylmalonic acid in all 14 children, of methylsuccinic acid in 9, of glutaric acid in 8, and of adipic acid in 7. High-pressure liquid chromatography of urinary acylcarnitines was done in 8 patients. All 8 had a high excretion of isobutyryl, 3 of n-butyryl,1 of2-methylbutyryl,1 of isovaleryl, and 2 of acetyl carnitine. There was a carnitine deficiency in serum in 10
Gas-chromatography/mass-spectrometry
urine showed
Mspl,Sacl,Xmnl,Pstl, and Pvull refer to restriction endonucleases used (1 = major allele, 2= minor allele)
an
630
of 14
and in muscle in 6 out of 10 children. Muscle decreased in the 2 patients studied. Ql0 These urinary organic acid and acylcamitine profiles point to a multiple FAD-linked acyl-CoA dehydrogenase deficiency,2 predominating in the fatty acid &bgr;-oxidation pathway but also involving the" branched-chain aminoacid and lysine oxidation pathways. This apparent acyl-CoA dehydrogenase deficiency and the muscle carnitine deficiency in patients with SMA type II are probably secondary to denervation, as has been demonstrated in animal experiments.34 Carnitine deficiency may be due, partly, to intramitochondrial accumulation of acylcarnitines, followed by renal excretion.s The reduced availability of acetyl-CoA could aggravate already impaired muscle function in SMA type II. Treatment aimed at stimulating acyl-CoA dehydrogenase activity (riboflavin [an FAD precursor], coenzyme Qlo, Lcarnitine, and a low-fat/high-carbohydrate diet) has been given to 13 children for between 3 and 30 months (mean 16). In group 1, the 2 youngest children can now maintain a sitting position, 1 (the floppy infant) can stand up with support, 1 has been walking unaided since the age of 28 months, and the oldest patient, treated for only 3 months, has more hand skill. In group 2, 4 patients can now walk 700 m to 3-4 km. (One patient, who died of a Reye’s-like syndrome at age 6 years, was not treated.) In group 3, there was no improvement in the oldest child (11-5 years); 1 child, now aged 9-5 years, can walk unaided for 20 m. In the 2 others, progress has been impaired by contractures of hips and knees; however, their arms are stronger. In 2 patients forced vital capacity has improved. These first results are encouraging; however, we are well aware of the possibility of spontaneous improvement in such patients. Further studies are needed to assess the frequency of secondary metabolic defects among patients with SMA type II and to monitor long term the proposed treatment. Infants with SMA type I should also be screened for metabolic defects.6 Children with type III are less likely to exhibit the same metabolic profile because of the intense reinnervation process.4 out
patients,
coenzyme
was
Metabolic Unit, Paediatric Clinic, Hôpital de la Salpêtrière, 75651 Paris, France
incidence of 38-3 per 100 000 in the general population, based on a survey conducted in Ilorin, in 1988. Our estimated permanent disability secondary to dracunculiasis was based on an estimated 1988 population of 481 000 (projected from 1963 census). The total number of cases of guineaworm disease revealed in a 1988 village-by-village survey in Ilorin was 4568/ to give an annual incidence of 950 per 100 000. The survey was of good quality but even so some cases may have been missed. Muller3estimates the load of permanent disability resulting from guineaworm disease at 0.5% of cases per year, giving an estimated annual permanent disability rate of 5 per 100 000 population (0-005 x 950) in Ilorin in 1988. However, a recent study from Sokoto State reported dracunculiasis-related permanent crippling to be as high as 0-9% in that part of Nigeria.’ Even with the lower disability rate permanent disability from guineaworm disease in Ilorin in 1988 was 13% of that resulting from poliomyelitis, and cumulative permanent disability over 20 years would be at least 100 per 100 000, compared with 750 per 100 000 population over the same period for poliomyelitis. Estimates of the annual incidence in Africa range from 3320 0005 to 10 million6 cases. According to these estimates and Muller’s figure between 16 600 and 50 000 Africans are permanently crippled as a result of guineaworm every year. This disease, unlike poliomyelitis, is limited to seventeen countries in Africa. Poliomyelitis is estimated to lead to permanent disability in 168 000 children in Africa every year7 The variation in case incidence and permanent disability rates for guineaworm disease point to the need for well-designed surveys to defme the extent of permanent disability from this preventable disease. Improved case counting should also help provide a more accurate estimate of permanent disability. With the much more prevalent temporary disability caused by guineaworm disease this permanent disability is a considerable burden on endemic rural communities.8 Aggressive early efforts are needed by all countries with endemic dracunculiasis to conduct national searches for dracunculiasis and initiate eradication programmes. Global 2000 Inc, Carter Presidential Center, Atlanta, Georgia 30307, USA
JEAN-PAUL HARPEY
INSERM U75,
CHU-Necker, Paris
CHRISTIANE CHARPENTIER
INSERM U134, Hôpital de la Salpêtrière
Division of Parasitic Diseases, Center for Infectious Diseases, Centres for Disease Control,
MARION PATURNEAU-JOUAS
Atlanta, Georgia
R. IMTIAZ D. R. HOPKINS
E. RUIZ-TIBEN
Laboratory of
Neurophysiology, Hôpital Trousseau, Paris
FRANCIS RENAULT
INSERM U153, Paris
NORMA ROMERO MICHEL FARDEAU
1. Dubovitz V. Muscle disorders m childhood. London: WB Saunders, 1978: 146-90. 2. Frerman FE, Goodman SI. Glutanc acidemia type II and defects of the mitochondrial respiratory chain. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds The metabolic basis of inherited disease. New York: McGraw Hill, 1989: 915-31. 3. Jato-Rodriguez J, Liang C-R, Lin CH, Hudson AJ, Strickland KP. Companson of the intermediary metabolism of fatty acids in denervated and dystrophic munne skeletal muscle. J Neurol Neurosurg Psychiatry 1975; 38: 1083-89. 4. Bresolin N, Freddo L, Tegazzin V, Bet L, Armani M, Angelini C. Carnitine and acyltransferase in experimental neurogenic atrophies: changes with treatment J Neurol 1984; 231: 170-75. 5. Roe CR, Coates PM. Acyl-CoA dehydrogenase deficiencies. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease. New York: McGraw Hill, 1989. 889-914. 6. Kelley RI, Sladky JT. Dicarboxylic aciduria in an infant with spinal muscular atrophy. Ann Neurol 1986; 20: 734-36.
1 Parakoyi B, Babaniyi O. Incidence of neonatal tetanus and polio m Ilorin LGA, Kwara State, Nigena 1988. Epidemiol Bull WHO/AFRO 1989, 5: 15 2. Anon. Dracunculiasis: Nigeria. Wkly Epidemiol Rec 1989; 64: 207-10. 3 Muller R. Guinea worm disease: epidemiology, control, and treatment. Bull WHO 1979; 57: 683-89 4. Kabiru, Abdullahi. Guinea worm infection: a case study of Kiri-manai villae in Gwadabawa local government area of Sokoto State, Nigeria. Ibadan: Ibadan University Press, 1988: 38. 5. Watts SJ. Dracunculiasis in Africa in 1986: its geographic extent, incidence, and at-risk population. Am J Trop Med Hyg 1987; 37: 119-25 6. Duke BO. Filariasis. WHO informal report/TDR 1976. Geneva: WHO, 1976. 7 Foster SO, Kesseng-Maben G, N’jie H, Coffi E. Control of poliomyelitis in Africa. Rev Infect Dis 1984; 6 (suppl 2): S433-37. 8. Smith GS, Blum D, Huttly SRA, Okeke N, et al. Disability from dracunculiasis: effect on mobility. Ann Trop Med Parasitol 1989; 83: 151-58
Diagnostic value of free subunits of serum gonadotropin in testicular cancer
chorionic
SIR,-The importance of human chorionic gonadotropin (hCG) as
Permanent
disability from dracunculiasis
SIR,-Several studies have reported on the prevalence of but permanent disability resulting from poliomyelitis’ dracunculiasis (guineaworm disease), another preventable cause of permanent disability, has not received the same attention. We have compared estimates of the permanent disability associated with poliomyelitis and that associated with guineaworm disease in the Ilorin local government area, Kwara State, Nigeria. Parakoyi and Babaniyil reported a prevalence rate for
poliomyelitis
lameness of 8-4 per 1000
population
and
an
annual
marker for testicular cancer has long been recognised.’ diagnostic and prognostic value of serum free &bgr;-subunit (hCG&bgr;) and especially of free a-subunit (hCGa), which is common to all human glycoprotein hormones, is still debated.2-4 We have developed highly sensitive and specific immunoenzymometric assays (IEMA) for free hCGcx, free hCG&bgr;, and holo-hCG with a panel of monoclonal antibodies produced in our laboratory.’ The established two-site IEMAs for the quantification of hCGx,
a tumour
The
hCG&bgr;, and holo-hCG showed sensitivities of between 8 and 10 pg/ml. The crossreactivities with holo-hCG in the IEMAs for the free ot-subunit and &bgr;-subunit were less than 0-1% and 0’01%,
