IJE Advance Access originally published online on July 23, 2007
International Journal of Epidemiology 2008 37(1):42-45; doi:10.1093/ije/dym140
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Commentary: Sibling trials in Banbridge, County Down
Department of Epidemiology and Public Health, The Queen's University of Belfast, UK.
E-mail: a.evans{at}qub.ac.uk
Accepted 7 June 2007
The market town of Banbridge in County Down, Northern Ireland, is built astride a drumlin (‘little back’ or hill). It was dumped during the last Ice Age as boulder clay when the great ice sheet scraped rocks from the Ulster hills on its inexorable push south. Along with tens of thousands of other drumlins it forms the celebrated landscape, which Estyn Evans compared to "... a necklace of beads some thirty miles wide suspended between Donegal Bay (in the west) and Strangford Lough (in the east)."1 It was near Banbridge town that the balladeer in an old song "first set eyes" on the object of his amorous aspirations: "She's young Rosie McCann from the banks of the Bann, She's the Star of the County Down."2
Banbridge has a curious, walled cutting in the main street, which was completed in 1834 to ease the gradient of the drumlin.3 It was excavated after it was threatened that the Belfast-Dublin Stage Coach would be re-routed to avoid the steep incline. It also boasts a fine Memorial to Captain Francis Rawdon Moira Crozier (1796–1848) who perished with Sir John Franklin while searching for the North-West Passage.4 The statue is guarded by four keening polar bears (Figure 1).
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These are not the only claims which Banbridge has to fame. Two unique medical trials were carried out here on two pairs of siblings, one male and the other female, and both pairs had inborn errors of metabolism.
In 1942, Dr James Deeny, a General Practitioner (Figure 2), who graduated from The Queen's University of Belfast in 1928,5 became interested in Vitamin C,6 which, discovered by Szent-Gyorgi a few years earlier, was just becoming affordable enough to prescribe.7 He thought that he had observed a beneficial effect in a patient with congestive heart failure, but his report was not taken seriously by the local cardiologists. One morning, during surgery hours, he saw a deeply cyanosed man walk past his window. Afterwards, he went down to the local police station to find out the identity of blue man. He was told that there was not just one blue man, but two blue brothers: Fred and Russell.
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James Deeny called on the brothers and asked them if they would like to become pink. Recalling his previous problems with doubting higher medical authority, he opted for a more scientific approach, treating the elder brother, Fred aged 29 years, with, what were for the period, fairly hefty doses of Vitamin C, and keeping the younger brother, Russell aged 19 years,7 as a control.6 This proved quite successful as, after about three weeks, the treated brother was a pretty normal colour. At last, with visible proof in hand, James tried the sceptical cardiologists again.7 While the appearances were irrefutable, it was also clear that the cause of the cyanosis was not of cardiac origin, as their hearts were normal, and the younger brother could play hockey.7
The brothers were taken to the Department of Physiology, where Dr Quentin Gibson was called on to examine them. Professor Henry Barcroft arranged to have the Russell's skin colour recorded by an artist during treatment with Vitamin C. Their initial excitement cooled once it was found that other investigators had already reported that Vitamin C could reduce methaemoglobin in a patient with methaemoglobinaemia.8 Subsequently Gibson sought the biochemical fault, ingeniously employing the guinea pig as a model, which, in common with man, cannot synthesize its own Vitamin C. In 1948 he described the aberrant pathway, the defect lying in the enzyme which catalyses the interaction between coenzyme 1 and methhaemoglobin,8 thereby describing the first heredity trait involving a specific enzyme deficiency.9 In 2002, Percy et al.,9 by tracing the brothers, identified the mutations responsible for their recessive congenital methaemoglobinaemia.
Interestingly, studies of the efficacy of Vitamin C in treating the common cold have employed a paired design in monozygotic twins.10 Monozygotic twins have identical genomes, so this approach provides the perfect control in teasing out any environmental contribution.
One other aspect of Dr Deeny's trial deserves comment: it serves to show that Sackett's dictum11 that, "Samples which are too small can prove nothing; samples which are too large can prove anything", does not hold good when the treatment effect is very large. This was also true for the small numbers on which James Lind demonstrated the anti-scorbutic benefits of citrus fruit in the Royal Navy in 1747.12
The other trial was conducted by Claude Field who graduated from the Queen's University in 1942. As a Consultant Paediatrician at Belfast City Hospital in 1959, he was attending his weekly General Clinic in Banbridge Hospital, where he first saw Patricia, aged 6 years. She had been referred from the nearby Castlewellan area, and had had three convulsive episodes for which no cause could be found. She was the first child, as her mother had had two previous miscarriages.13 Her development had been slow, but at 3 years she was thought to be quite fit. Talking began at 5 years but she only had about a dozen words of speech. She was co-operative and could obey simple commands. She was placid, plump and obviously mentally backward.13 She had fine, dry, sparse blond hair and blue eyes with iridodonesis due to posterior dislocation of both lenses. Her complexion was fair with bright pink patches of colour on each cheek and, elsewhere, covered with erythematous blotches resembling the pattern of erythema ab igne. Soon afterwards, her younger sister, Pauline, was brought to hospital. She was 4-years old, resembled her elder sister, had walked at 15 months but had not yet started to speak. She had had a major motor seizure.
Claude Field knew that he had found a condition which he could not identify. Literature searches failed to find a satisfactory label so he embarked on extensive investigations. Chromosome analysis revealed nothing untoward. Samples of urine were sent to Nina Carson and Desmond Neill at the Royal Victoria Hospital, Belfast, who were carrying out a survey of metabolic abnormalities in mentally handicapped individuals in the Province.13 Initial testing failed to identify anything, but Claude persisted in sending samples. The cyanide nitroprusside test for cystine was found to be positive and amino acid screening showed a spot in the cystine position. However, as this was not accompanied by the other amino acids found in cystinuria, further urine specimens were sent to Prof. Charles Dent at University College Hospital, London. In his laboratory, amino acid chromatography on these and subsequent 24 h specimens showed that the amino acid was not cystine but homocystine.
On the best evidence available at the time, it was thought that the disorder was probably caused by cystine deficiency due to a problem with methionine degradation. It was, therefore decided to feed a large dose of cystine to Pauline, with Patricia acting as the control. Pauline was put on 1 g tablets of cystine, three times a day. Her course was not straightforward as she developed paralysis of the left leg following a presumed fit. After a break in treatment and then resumption for a further period, it was apparent that no benefit had been achieved. At one stage, Pauline's mother told Claude that Pauline had uttered a word. He enquired what the word was. ‘Oh it was nothing’ came the reply. Eventually, Claude managed to coax the mother into divulging what turned out to be a moderately offensive expletive. Pauline did not utter any further words.
Claude Field presented the first two cases of homocystinuria to be recognized at the 10th International Congress on Paediatrics in Lisbon, Portugal in September 1962.14 Carson and Neill13 published a fuller description of the two cases later that year as part of their survey of mentally backward children. By the next year, eight cases had been identified15 and by 1965, 10.16 Sadly, the two little sisters are long since dead.
Hyperhomocysteinaemia has since become a burgeoning research area, with a bearing on several diseases.17 Little did Claude and his colleagues suspect this at the time.
It may strike readers from outside this island as bizarre that Quentin Gibson should later pose the question,7 in relation to the deeply cyanosed brothers, that ‘You might wonder why with only 5000 people (the population of Banbridge in 1942), Dr Deeny did not know them already. The brothers were Protestants, and Dr Deeny a Catholic’. During World War II there was no conscription in Northern Ireland and Dr Deeny, as a devout Catholic,5 would not have volunteered for service. In fact, there was no war at all in the Republic of Ireland at the time, merely ‘The Emergency’, as the Republic of Ireland had declared itself neutral.18 There is a strange symmetry to the fact that Claude Field, coming from the Protestant tradition, served in the British Navy during the War (Figure 3), and conducted a trial in two catholic sisters in Banbridge. The estrangement of the two communities in Northern Ireland has long been endemic and, until 1971,19 even the medical students at the Queen's University of Belfast were segregated by the appropriate persuasion of the hospital in which they gained their clinical experience.
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Was it pure coincidence that two trials in siblings should have been carried out in one small, rural, County Down, town? Conducting a trial in two individuals is about as small a study as is feasible, aside from the intra-individual approach. Moreover, they were conducted in two recessively inherited inborn errors of metabolism. Was there any reason why these conditions should be particularly common there? Certainly there was little social mobility at the time, particularly in rural areas, and the two traditions did not tend to mix. The Doctrine of ‘Ne Temere’, introduced in 1907,20 to dissuade Catholics marrying outside their religion was certainly followed. Consanguinity rates are not particularly high in comparison with other European countries, in the Catholic population at least.21 Probably dispensation for marrying a first cousin may have been more common in the Protestant tradition. In any case, social immobility, compounded by the presence of two religious groups who were disinclined to intermarry, served to limit the gene pool. It must be concluded, however, that here we are observing an incredible chain of coincidence, particularly as Claude Field was oblivious to James Deeny's earlier trial.
Acknowledgements
Thanks are due to Banbridge District Council for permission to reproduce Figure 1, and to the Deeny Family for permission to reproduce Figure 2. Thanks are also due to Jason Diamond and Deva Evans. I wish to acknowledge the privilege of having been taught by Claude Field when I was a medical student, and that he is my wife's wonderful uncle.
References
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