Results

One hundred and three initial notifications were received through the Surveillance Unit. Follow up led to the identification of 55 patients. This total excluded a child of an American family serving in the US air force; a child who was seen in the UK but who had been diagnosed in Germany, where his family was stationed with UK armed forces; one case where the diagnosis was not adequately confirmed; and six cases that had been reported retrospectively (diagnosed before February 1994). Much of the discrepancy between the number of returns and the number of patients was a result of multiple reporting, reflecting the tendency for MCAD deficient patients to be referred to specialist centres either before or after diagnosis. The laboratories reported an additional seven cases, giving 62 in total. Fifty seven of the cases were diagnosed in England and five in Scotland; no reports were received from Wales, Northern Ireland, or the Irish Republic.

Table 1 summarises the reasons for diagnostic investigation. Forty six of the patients were investigated as a result of an acute metabolic decompensation or unexpected death. Hypoglycaemia was recorded in 37 of these. Encephalopathy was noted in 23 cases, although criteria for reporting this may have been interpreted differently because some of the duplicate reports disagreed.

In the 46 cases that presented with acute illness, 39 were diagnosed after a single episode, all but four within 30 days. Six patients were diagnosed after a second acute episode, between 39 and 369 days after the initial illness, and one patient was diagnosed after his third acute episode at the age of 12 years. Table 2 summarises the outcome at the time of reporting.

The 62 cases diagnosed during the period of our study came from 54 families. These families contained another six confirmed cases of MCAD deficiency, diagnosed before this study, and five other children had died in infancy, all of whom probably had MCAD deficiency. Including these, 58 infants had had one or more metabolic crises or had died suddenly; the ages at which the first such event occurred were reported in 56 cases and are plotted in fig 1. Seven patients, three of whom died, became ill in the neonatal period.

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Figure 1

Age of patients at their first episode diagnosed with or suspected of having MCAD deficiency (n = 56). Fatal episodes are shown by open circles (some of the data points are obscured by overlap.) Information is missing on two cases diagnosed postmortem.

DNA analysis for the common (G985) MCAD mutation2 had been performed in 45 families. In 36, the affected children were homozygous for G985, and in the other nine families the children were heterozygous. Thus, 90% of mutant alleles were G985, in agreement with previous estimates.13 The sex ratio in confirmed cases was 1.0.

Discussion

This study has three main limitations: (1) it is based on diagnosed cases only, estimating minimum incidence but giving no firm data on the proportion of cases that remain undiagnosed or asymptomatic; (2) the short follow up period probably leads to an underestimate of the frequency of long term sequelae; and (3) some data are incomplete and there may be systematic underreporting of symptoms in the newborn period. Nevertheless, the survey has provided sufficient information on the current status of MCAD deficiency in the UK to allow comparison with other reported experience and to confirm the continuing high rate of mortality.

INCIDENCE

There has been much debate about the true incidence of symptomatic cases of MCAD deficiency. An estimate of the incidence of the biochemical condition can be calculated from the G985 heterozygote frequency of the population in question, correcting for the observed frequency of G985 in diagnosed cases. Almost universally, the number of cases diagnosed is substantially lower than the calculated incidence.3 14-16 The shortfall must be accounted for by asymptomatic individuals and/or by a low rate of diagnosis of symptomatic cases, but the relative magnitude of these effects is unknown. Asymptomatic cases appear to be moderately common. The father in one of the families included in this survey was homozygous for the G985 mutation but had never had any symptoms.6 In three other families, diagnosis of the index case led to the identification of MCAD deficiency in four siblings over 2 years of age (range, 6–23 years) who had not had significant metabolic decompensation, although in two sisters there had been indications of fasting intolerance.17 In four families with an unexplained infant death, MCAD deficiency was diagnosed in a subsequent symptomatic sibling. The only evidence that most untreated cases of MCAD deficiency will eventually have symptoms comes from experience in the Trent region in the UK. Here, MCAD deficiency has been of long standing interest and the number of cases diagnosed in an eight year period was close to the number calculated from heterozygote frequency.3

There is a geographical variation in the incidence of MCAD deficiency within the British Isles. The lack of reported cases from the Irish Republic probably reflects the relative rarity of MCAD deficiency which, calculated on the basis of the G985 gene frequency, is approximately 1.7 in 100 000 births (PD Mayne, Temple Street Children’s Hospital, Dublin, personal communication, November 1997). Our survey reported 4.0 cases/100 000 births in Scotland, despite a fairly low frequency of the G985 mutation in West Scotland.18 For England as a whole, 4.5 cases/100 000 births were reported. These figures might overestimate the “steady state” rate of diagnosis because two siblings were diagnosed rather late, 10 years after the first episode in the index case, while another family with three affected siblings was investigated for MCAD deficiency seven years after the death of the index case.17 Calculated incidences of MCAD deficiency are 11.3/100 000 for Shropshire, Herefordshire, and Worcestershire and 4.5/100 000 for the Trent region.3 Although there is probably still some degree of underdiagnosis in the UK, comparison of the current overall figures with the diagnosis rate of 1.8/100 000 in the West Midlands region in 1987–94 (16% of the expected number)3 suggests that a greater proportion of MCAD deficient children than previously are being identified.

CLINICAL PRESENTATION

All but two of the clinically affected cases reported presented with typical symptoms of MCAD deficiency.4 The age at first episode ranged from 2 days (three cases) to 4.39 years, with a median of 1.1 years (fig 1). Neonatal presentation of MCAD deficiency is being increasingly recognised,19 20 but the proportion recorded in this survey (seven in a total of 73 suspected or confirmed cases) is much lower than that found in the New South Wales series, where eight of the 20 patients had had significant hypoglycaemia requiring at least intravenous glucose at an age of 1–3 days.14 It is likely that neonatal episodes were significantly underreported in this survey because there was no systematic review of neonatal records.

DIAGNOSIS AND OUTCOME

The only previous study of unselected patients with MCAD deficiency from a defined population is that of Wilckenet al in New South Wales.14 The series of Iafolla et al was based on a diagnostic service, although 112 of the 120 patients surveyed were from the USA.4 Both these studies were retrospective, spanning up to 17 years and, not surprisingly, current UK experience with diagnosis appears to be better: 35% of the patients described by Iafolla et al and 25% of those described by Wilcken et al had more than one episode before diagnosis, compared to 11% in our study. More than half of the patients in our study who presented with an acute episode were diagnosed within 30 days, compared with an average delay of 1.8 years in the series of Iafolla et al. This probably reflects increased clinical awareness of MCAD deficiency and improved access to appropriate laboratory services. Despite the improvement in diagnosis and paediatric intensive care over recent years, mortality remains high. Ten of the 62 cases diagnosed during our survey period died during the initial attack and if affected siblings and suspicious deaths are included mortality of affected children in these families was 17 of 73. This compares with mortality rates of 19% and 25% in the New South Wales and USA studies, respectively.

Both the New South Wales series14 and the USA series4 record high levels of disability in patients surviving an acute attack. Five of the 15 New South Wales survivors had some degree of handicap. The USA survivors showed cerebral palsy (9%), seizure disorder (14%), muscle weakness (16%), speech disability (22%), and/or abnormal results on formal psychodevelopmental assessment (32%). In our survey, three of the 36 patients surviving one or more attacks showed signs of neurological damage in the immediate post-recovery period and three others had developmental delay or learning difficulty. These apparently good results may be spurious, however, because a longer follow up period would be necessary to reveal the milder neurodevelopmental deficits.

Our conclusion from this survey is that, despite increasing awareness of MCAD deficiency and more efficient diagnosis, mortality remains essentially unchanged and morbidity is still considerable. Although a few are diagnosed in the neonatal period, most patients have their first detected attack after the age of 3 months and would benefit from early diagnosis by neonatal screening. The number of cases reported suggests that the frequency of MCAD deficiency in England and Scotland is high enough to justify inclusion in the neonatal screening programme.11