information on continence by doctors, and to some extent by nurses, but also such information as is recorded is often inaccurate. Department of Geriatric Medicine, University of Liverpool, Royal Liverpool Hospital, Liverpool L69 3BX, UK


DT, Hewer RL. Outlook after acute stroke: urinary continence and loss of consciousness compared in 532 patients. Q J Med 1985; 56: 601-08. 2. Barer DH. Continence after stroke: useful predictor or goal of therapy? Age Ageing 1989; 18: 183-91. 1. Wade

Malignant hyperthermia and Marinesco-Sjögren syndrome SIR,-Dr Elechi and Dr Dakaraju (Nov 9, p 1206) report malignant hyperthermia (MH) in three patients with Hirschsprung’s disease, and point out its association with other neuromuscular syndromes. Prompted by their contribution we report a clinical observation that is possibly related to MarinescoSjögren-syndrome-associated MH. The autosomal recessive Marinesco-Sjogren syndrome consists of congenital cataract, cerebellar ataxia (with or without cerebellar atrophy), and some mental retardation and neurogenic myopathy. 1,2 Among the published cases, MH developed in one child during cataract surgery.3 We are caring for two families of Romanian gypsy descent, both of which include two children with Marinesco-Sjogren syndrome. In one boy, the clinical course so far has been compatible with the myopathic type of the syndrome. At 8 years of age subsequent to an upper-respiratory-tract infection an acute generalised myopathy developed with profound muscle weakness and tenderness and a hundredfold increase from normal serum creatine kinase, which returned to normal values rapidly with steroid therapy. Muscle biopsy showed features of chronic neurogenic damage that had been noted previously, and inflammatory changes were absent. Muscle power was slowly regained in four months. During this time however, severe talipes developed. The other pair of siblings, who are unrelated to this boy but are of the same ethnic origin, were described by their parents as having muscle pain and weakness with every febrile illness; creatine kinase in these children was slightly raised on several occasions. These findings suggest that Marinesco-Sjogren syndrome should probably be added to the growing list of neuromuscular diseases carrying an increased risk of MH.4-7


Kinderpoliklinik der Universitat, D-8000 Munchen 2, Germany 1. Superneau

D, Wertelecki W, Zellweger H, Bastian F. Myopathy in MarinescoSjogren syndrome. Eur Neurol 1987; 26: 8-16. 2. Serratrice G, Gastaut JL, Dubois-Gambarelli D. Amyotrophie neurogène périphérigue au cours du syndrome de Marinesco-Sjögren. Rev Neurol 1973; 128: 432-41. 3. Todorov A. Le syndrome de Marinesco-Sjoren: première étude anatomoclinique. J Génét Hum 1965; 14: 197-233. 4. King JO, Denborough MA. Anaesthetic-induced malignant hyperpyrexia in children. J Pediatr 1973; 83: 37-40. 5. Brownell AKW, Paasuke RT, Elash A, et al. Malignant hyperthermia in Duchenne muscular dystrophy. Anesthesiology 1983; 58: 180-82. 6. Proster-Iskenius U, Waterson JR, Hall JG. A recessive form of congenital contractures and torticollis associated with malignant hyperthermia. J Med Genet

1988; 25: 104-12. G, Isaacs H. An association between certain congenital abnormalities and the malignant hyperthermia trait. S Afr Med J 1990; 77: 570-74.

7. Gericke



spasmolytic drug

irreversible inhibitor of y-aminobutyric SIR,-Vigabatrin, acid (GABA) transaminase, is used in the treatment of epilepsy, especially complex partial seizures. We report here on our experience with this drug in the symptomatic treatment of spasticity due to metabolic diseases with leukodystrophyl in six childrenthree with metachromatic leukodystrophy, two with Krabbe disease (globoid-cell leukodystrophy), and one with Nieniann-Pick disease type C. These lysosomal diseases, at least in their spastic stage, are accompanied by decreased to borderline low CSF free

’GABA levels.2,3 This is most probably a secondary feature that could be responsible, at least in part, for the spasticity. The age of the patients at the start of the therapy ranged from 3 months to 5 years. Vigabatrin was given as monotherapy for 10-44 months. It was administered at a daily dosage of 25-100 mg/kg in two divided doses. In all patients this resulted in a significant and persistent reduction of spasticity and hyperexcitability, permitting better nursing of the children and greatly increasing their comfort. This effect was especially impressive in the patients with Krabbe disease. In two patients, weakness and drowsiness observed at 75 mg/kg disappeared when the dose was lowered to 50 mg/kg daily. This spasmolytic effect of vigabatrin needs evaluating in a larger series of patients. An important question is whether the drug is also beneficial in spasticity of other than metabolic origin.

Department of Paediatrics, University of Leuven, 3000 Leuven, Belgium


1. Scriver

CR, Beaudet AL, Sly WS, Valle D. The metabolic basis of inherited disease. New York: McGraw-Hill, 1989. 2. Jaeken J, Casaer P, Haegele K, Schechter PJ. Normal and abnormal central nervous system GABA metabolism in childhood. Inherited Metab Dis 1990; 13: 793. 3. Carchon HA, Jaeken J, Jansen E, Eggermont E. Reference values for free gamma-aminobutyric acid determined by ion-exchange chromatography and fluorescence detection in the cerebrospinal fluid of children. Clin Chim Acta 1991; 201: 83.

All-trans retinoic acid in leukaemia


SIR,-Dr Koller and colleagues (Nov 2, p 1154) describe the restoration of all-trans retinoic acid (ATRA) sensitivity by concurrent or alternating therapy with interferon-a-2b (INF&agr;) in a patient with acute promyelocytic leukaemia (APL). As in-vitro support for their observation they cite their 1990 paper on cultured myeloid leukaemia cell lines not our earlier evidence for an interaction between ATRA and INFa in fresh leukaemic cells from two patients with APL.1 Although we too are investigating this potentially useful combination in APL, we would mention as a warning our recent experience with a patient with a promyelocytic blastic crisis of chronic myelogenous leukaemia (CML). As in most cases of APL, this patient had a striking clinical response to ATRA,3but, after relapse on ATRA, there was no response to increased ATRA with or without INFfx. Clonogenic cells from this patient at the time of relapse remained sensitive to the inhibitory effect of ATRA and INFfx individually, but there was no evidence of a positive interaction between these agents in vitro, as we have noted in several other cases of CML in accelerated phase or blastic crisis.3 The variant results in advanced CML and APL may reflect different modes of action of ATRA and INFfx in these diseases and emphasise the need for further correlative clinical/laboratory studies in this promising area. Montefiore Medical Center and Albert Einstein Cancer Center, Bronx, NY 10467, USA 1.


Gallagher RE, Lune KL, Leavitt RD, et al. Effects of interferon and retinoic acid on the growth and differentiation of clonogenic leukemic cells from acute myelogenous leukemia patients treated with recombinant leukocyte- &agr;A interferon. Leukemia

Res 1987; 11: 609-19. 2. Wiernik PH, Dutcher JP, Paietta E. et al. Treatment of promyelocytic blast crisis of chronic myelogenous leukemia with all trans-retinoic acid. Leukemia 1991; 5: 504-09. 3. Sagayadan G, Dutcher J, Wiernik P, et al. Effect of trans-retinoic acid and interferon&agr; on clonogenic chronic myelogenous leukemia blast crisis cells. Proc Am Assoc Cancer Res 1991; 32: 32.


How many genetic diseases? SIR,—Claims that

genes are "the ultimate explanation for the and that being" they "define a human being", are "the blueprint for life", and may eliminate homelessness have been made.1,2 Such remarks may mislead the public about the limitations of and benefits to be derived from the study of human genetics. Another distortion needs discussion too. Paul Berg, Nobel



Laureate, has stated that "many if not most human diseases are clearly the result of inherited mutations" in presumably one or more of 100 000 or so genes.’ Many commentators note that there are 3000-5000 human genetic diseases,3,4 a figure that I believe is derived from the total number of entries in the McKusick compendium.5 Listings in this invaluable book show that many of the mendelian traits described are not diseases. For instance, "inability to smell musk" (254150) or "proneness to appendicitis" (107700) are not illnesses. Nor are the genetic loci encoding "arm folding preference" (107850), "ability to move ears" (129100), and "stammering" (184450) likely to be found amongst the 3 billion base-pairs of haploid DNA. Some diseases do have a simple genetic basis and others will have their cause illuminated by human genomic studies. But, the number of clinically important genetic disorders is not known and it is misleading to claim otherwise. Division of Genetic Medicine, California Pacific Medical Center, Box 7999, San Francisco, California 94120, USA


1. Beckwith J. The hegemony of the gene: reductionism in molecular biology. In: Sarkar S, ed. The philosophy and history of molecular biology Dordrecht: Kluwer (in

press). 2. Billings P. Promotion of the human genome project. Science 1990; 250: 1071. 3. Wexler N. Disease gene identification: ethical considerations. Hosp Prac 1991; 26: 113-20. 4. Callahan D. What are the goals of medicine?: understanding the genome project. Presented at conference on the genetic prism: understanding health and

responsibility (University of California, April, 1991). 5. McKusick V, Francomano C, Antonarakis S. Mendelian inheritance in man: catalogs of autosomal dominant, autosomal recessive and X-linked phenotypes, 9th ed. Baltimore. Johns Hopkins University Press, 1990.

Haemofiltration in

patients with fulminant hepatic failure

SIR,—Mortality of patients with fuhninant hepatic failure (FHF) who progress to coma remains high despite advances in supportive therapy. Over the years many techniques have been tried to improve survival, including exchange transfusion, plasma exchange, perfusion through animal livers, charcoal haemoperfusion, and continuous haemofiltration with or without haemodiafiltration. All treatments initially reported success, but


with time and controlled evaluation no real increase in survival has yet been reported.2 This is shown by Inaba and colleagues’3 report of a patient with FHF who was treated by continuous haemofiltration and yet died of hepatic failure. If acute renal failure develops in FHF mortality rate is increased. In this setting the treatment of renal failure with continuous haemofiltration, with or without haemodiafiltration, is preferable to conventional intermittent machine haemodialysis and haemofiltration, because it causes less disturbance than other treatments with respect to cardiac output, tissue oxygen delivery,4 intracranial pressure, and cerebral perfusion pressure.5 Haemofiltration with highly permeable membranes will allow the loss of so-called middle molecules. Some workers have suggested that this may result in the removal of key toxins such as ammonia

gamma-aminobutyric acid (GABA), and so cause an improvement in conscious stated However, haemofiltration, whether by intermittent machine or continuous pumping with or without haemodiafiltration, will only remove molecules that can be freely filtered from plasma. Thus, the losses are dependent on the plasma concentration and the volume filtered. For example, ammonia accumulates in FHF, and the losses achieved by these techniques indicate the plasma concentration (figure). No significant difference in ammonia concentration was detectable in blood samples taken on entry to and exit from the dialysis membrane with any of the modes of renal replacement therapy studied. The actual daily removal of ammonia achieved is small when compared with the total body ammonia pool and the rate of ammonia generation. These small losses are unlikely to affect cerebral function. Similar results have been found for plasma concentrations of aminoacids and GABA.’ and

Since haemofiltration has not been shown to substantially affect cerebrospinal fluid or cerebral concentrations of ammonia or GABA,6treatment with various modes of haemofiltration with or without haemodiafiltration is unlikely to substantially affect overall outcome, which will depend eventually on the degree of hepatic damage and the underlying aetiology.l,2 Patients with FHF should preferably be referred at an early stage to specialist centres so that decisions appropriate to individual patient outcome can be made and the need for acute orthotopic liver transplantation assessed. Department of Renal Medicine, Southmead General Hospital,



Bristol BS10 5NB, UK 1.

O’Grady JG, Alexander GJ, Hayllor KM, Williams R. Early indication of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97: 439-45. 2. O’Grady JG, Gimson AES, O’Brien CJ, Pucknell A, Hughes RD, Williams R. Controlled trials of charcoal haemoperfusion and prognostic factors in fulminant hepatic failure. Gastroenterology 1988; 94: 1186-92. 3. Inaba S, Kishikawa T, Zaitsu A, et al. Continuous haemoperfusion for fulminant hepatic failure. Lancet 1991; 338: 1342-43. 4. Davenport A, Will EJ, Davison AM. Continuous vs intermittent forms of haemofiltration and/or dialysis in the management of acute renal failure in patients with defective cerebral autoregulation at risk of cerebral oedema. Contrib Nephrol 1991; 93: 225-33. 5.

Will EJ, Losowsky MS, Swindells S. Continuous arteno-venous haemofiltration in patients with hepatic encephalopathy and renal failure. Br Med J

Davenport A,

1987; 295: 1028. Opolon P, Huguet CI, Nusinovici V, et al. Effect of middle molecule removal on encephalopathy during acute liver failure. Eur Soc Artif Organs 1982; 2: 228-35. 7. Davenport A, Roberts NB. Ammo acid losses during haemofiltration. Blood Purif 6.

1989; 7: 192-96.

Origin of AIDS SIR,—In the Nov 28 issue of Nature Charles Gilks, in a commentary entitled "AIDS, monkeys, and malaria", suggested that primate retorviruses may have been passed on to man or other monkeys as a result of experiments with primate malarias. In the same week appeared a Lancet editorial on New Glands for Old, referring to the work of Serge Voronoff (1925) who transplanted monkey glands into the scrota of hypogonodal males. Might these males have been infected with HIV? Voronoff described a 65-year-old man who needed a second graft "having been over-prodigal of the vital energy supplied him by the old one". It would be tragic if this transplantation were to have been one source of the AIDS epidemic. Department of Clinical Chemistry, University Hospital, 2333 AA Leiden, Netherlands


Shades and colours SIR,—With respect to your Nov 23 editorial on colour vision and visual discrimination, I recall that when I was living in rural Africa a partly colour-blind colleague could sometimes see wild animals which were so camouflaged that those of us with normal colour vision could not see them until they moved. Disabilities sometimes bring advantages with them. Relation between blood and

ultrafiltrate/dialysate ammonia.

Haemofiltration by intermittent mach!ne=0, by continuous pumping=A, and with haemodiafiltration= X . r=0 99, p

How many genetic diseases?

1603 information on continence by doctors, and to some extent by nurses, but also such information as is recorded is often inaccurate. Department of...
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