Lilias Barron

Maternal serum-alpha-fetoprotein measurements as an early indicator of low birth-weight.

In a prospective trial of 4224 pregnancies, 103 women had serum-alpha-fetoprotein (A.F.P.) above 2-3 times the median value for their stage of gestation. 10-7% of these delivered infants with birth-weights less than 2-5 kg. This was significantly greater than the rate of 4-2% for low-birth-weight infants in the general population. At higher multiples of the median serum-A.F.P. value the proportion of pregnancies leading to low-birth-weight infants was even greater. It is suggested that early identification of pregnancies with high risk of premature delivery may be an important corollary of maternal serum A.F.P. screening.

A study of the Huntington's disease associated trinucleotide repeat in the Scottish population.

Accurate measurements of a specific CAG repeat sequence in the Huntingtons disease (HD) gene in 337 HD patients and 229 normal controls from the Scottish population showed a range from 35 to 62 repeats in affected subjects and eight to 33 in normal subjects. A link between early onset of symptoms and very high repeat number was seen. For HD patients with the most common affected allele sizes (39 to 42 repeats) absolute repeat size was a poor index for the age at onset of symptoms. There was variability in the transmitted repeat size for both sexes in the HD size range. We observed a significant increase of repeat size for paternal transmission of the disease and greater instability for paternally transmitted CAG repeats in the HD size range.

Prospective prenatal diagnosis of cystic fibrosis.

An immunoassay based on monoclonal antibodies with specificity for the three major isoenzymes of alkaline phosphatase (ALP) has been used in second-trimester prenatal diagnosis of cystic fibrosis (CF). 140 pregnancies with a 1-in-4 risk of CF were assessed prospectively, and outcomes are reported for 100 of these. In 9 cases the diagnosis could not be confirmed or excluded, in 65 cases the infant was normal, and in 15 the infant had CF. In the remaining 11 cases, in which the pregnancy was terminated, the diagnosis of CF was confirmed in the abortus by measurement of albumin and protease levels in meconium scraped from the fetal ileum. Of the 26 cases of CF in the prospective series, 23 (88%) had values of intestinal ALP below half the median value for the corresponding week of gestation. Among those with normal outcomes 3 of 65 (4.6%) were below half-median. When prospective and retrospective data are summed the sensitivity of the test was 91% (39 of 43) and the false-positive rate 6% (5 of 81). This is probably an acceptable form of prenatal diagnosis of CF for the high-risk mother.

Monoclonal antibodies to human α-foetoprotein: Analysis of the behaviour of three different antibodies

Three mouse monoclonal antibodies directed to different epitopes on human alpha-foetoprotein have been produced. Two are of IgG1 subclass and the third is IgA. The polyethylene glycol-dependent immunoprecipitation system, designed for conventional antisera, had to be adapted before reproducible results could be obtained with the reagents. In this adapted system, as well as in a radioimmunoassay using solid-phase second antibody, a mixture of the 3 monoclonal antibodies exhibits cooperativity. However, the sensitivity of the radioimmunoassay with pooled monoclonals is not good as that of conventional antiserum. Low affinity monoclonal antibodies have been used for immunopurification of the antigen, whilst the high affinity one is useful for antigen quantitation in a labelled antibody-dependent system which requires absolute antibody specificity.

Prenatal diagnosis of cystic fibrosis by microvillar enzyme assay on a sequence of 258 pregnancies.

SummaryPrenatal diagnosis of cystic fibrosis by microvillar enzyme assay on amniotic fluid supernatant has been carried out on 258 sequential pregnancies with a 1 in 4 recurrence risk, all with known outcome. In general the three enzymes evaluated, γ-glutamyltranspeptidase, aminopeptidase M and the intestinal isoenzyme of alkaline phosphatase, showed a high degree of concordance. However, there were two unusual patterns of microvillar enzyme activity; in seven cases a low γ-glutamyltranspeptidase activity was associated with elevated values of intestinal alkaline phosphatase, and in ten cases there were isolated low values of intestinal alkaline phosphatase. The former pattern was found to be associated with cystic fibrosis in five cases, while the latter was associated with a normal outcome in all ten cases. A retrospective analysis of enzyme values suggested that the optimal system for minimizing false positives and false negatives was to define foetal cystic fibrosis as a sample where two of the three microvillar enzymes were below a cut-off of half the median value for the gestational week. If such scoring were applied to the cases where conventional microvillar enzyme patterns were observed, the false positive rate was 2.3% and the false negative rate 4.4% between 17 and 20 weeks of gestation.

Measurement of placental alkaline phosphatase in maternal plasma as an indicator of subsequent low birthweight outcome.

Summary. Placental alkaline phosphatase (P‐ALP) was measured by a specific monoclonal antibody‐based immunoassay in plasma samples of 117 women who subsequently were delivered of an infant of birthweight less than 2·5 kg. P‐ALP values > twice the normal median were found in 32% of maternal plasma samples from low birthweight cases in one scries and in 35% in another series, while in normal outcome controls the corresponding value was 8%. The differences were highly significant. The proportion of low birthweight cases with elevated maternal P‐ALP values appears to be very similar between 15 and 34 weeks gestation. At 16–18 weeks gestation there is a significant positive correlation (r = 0·40) between P‐ALP and maternal plasma alpha‐fetoprotein (AFP) values in low birthweight cases. The use of P‐ALP assay in combination with AFP assay appears to improve the detection of pregnancies with subsequent low birthweight outcome.

THE POTENTIAL OF MID-TRIMESTER MATERNAL PLASMA ALPHA-FETOPROTEIN MEASUREMENT IN PREDICTING INFANTS OF LOW BIRTH WEIGHT

Maternal plasma alpha‐fetoprotein (AFP) was measured at mid‐trimester in 113 women who subsequently were delivered of a singleton liveborn infant weighing less than 2·5 kg and in 113 matched controls whose infants weighed more than 2·5 kg. Plasma AFP levels were significantly higher in the subjects than in the controls, while 10 of the subjects and only 3 of the controls had values above 2·0 times the median. The higher AFP concentrations were seen both in pregnancies in which the outcome was a small premature infant and in those in which it was a small‐for‐dates baby.

Incoordinated thought and emotion in spinocerebellar ataxia type 8

Sirs: A new form of autosomal dominant spinocerebellar ataxia (SCA8) with incomplete penetrance due to a non-coding expansion of CTG repeats on chromosome 13q21 has been described in seven kindreds in the United States [1], in a series of six patients from Japan [2] and seven from Portugal [3]. Further studies have reported a number of healthy controls and elderly unaffected family members who do not have ataxia but nevertheless have large expansions at the gene locus [3–7]. We describe a mother and son with the SCA8 expansion with executive, visuospatial and affective problems in addition to an ataxic syndrome. We also discuss the degree to which these neuropsychiatric features could be a result of isolated cerebellar dysfunction, as part of the ‘cerebellar cognitive affective syndrome’ [8]. A 46-year old man (case 1) presented with a 5-year history of slurred speech and deteriorating memory and a 3-year history of mild progressive gait ataxia and impairment of manual dexterity. In addition, over 5 years his wife reported a marked change in personality with lability of mood throughout the day and aggressive outbursts, on one occasion leading to a near strangling, out of keeping with his previously placid demeanour. He had become highly methodical, inflexible and at times ritualistic about organising routine tasks such as eating and shaving or keeping appointments. He described difficulties remembering visual rather than verbal information and problems concentrating on more than one thing at a time. He had no relevant past history and had never abused alcohol or other drugs. He had become unemployed following an aggressive outburst at work. His wife commented that his personality change was a much greater problem than his dysarthria. At interview his mood was unusually buoyant with no evidence of depression, hypomania, anxiety or psychosis. He had impaired insight into his behavioural problems. His speech was dysarthric and dysprosodic with slowed repetitive tongue movements. He had a mildly ataxic gait but no detectable limb ataxia. Neurological examination was otherwise normal. His Mini-Mental State Examination (MMSE) score was 30/30. Neuropsychological testing is summarised in Table 1. There were significant deficits in tests of execLETTER TO THE EDITORS

PRENATAL DIAGNOSIS OF NEURAL-TUBE DEFECTS WITH A MONOCLONAL ANTIBODY SPECIFIC FOR ACETYLCHOLINESTERASE

An immunoassay for acetylcholinesterase (AChE), based on a monoclonal antibody (AE-2), gave the following results when applied to a panel of amniotic fluids: (a) among 651 samples with normal outcome and normal alphafetoprotein (AFP) values there were 2 (0.31%) false positives; (b) of 9 samples with normal outcome and raised AFP values 1 had a raised AChE titre; (c) all 48 samples from anencephaly cases had raised AChE values; (d) among 49 samples from open spina bifida cases (2 of which had normal AFP values), 48 had raised AChE titres. It is suggested that a monoclonal-antibody-based immunoassay may displace polyacrylamide gel electrophoretic analysis of AChE as a complementary test to AFP in prenatal diagnosis of neural-tube defects, since it is a quantitative test largely independent of operator skill and experience.

Predictive testing for Huntington disease : social characteristics and knowledge of applicants, attitudes to the test procedure and decisions made after testing

An investigation has been made of the social characteristics and knowledge and experience of Huntington disease (HD) for the first 80 individuals considering presymptomatic testing (applicants) at the medical genetics centres in Edinburgh and Glasgow and of attitudes to the test procedure and decisions made after testing for those who received a result. Sixty‐one percent of applicants were female and 31% were over 40 years old. Almost all had a symptomatic parent but 38% did not know HD was in their family until they were over 25 years old and 48% had never received genetic counselling. Thirty‐eight percent of applicants first heard of the test at the genetic clinic, 20% from a relative and 20% from the media, but none had received information from their GP. Thirty‐one applicants did not have the test because they voluntarily withdrew (17 individuals), their family structure was unsuitable or no informative result was possible (11 individuals), or they were diagnosed clinically as being affected (3 individuals). Those who voluntarily withdrew did not differ significantly from the 49 who received a result in social characteristics or knowledge and experience of HD. Twenty‐two individuals were found to be at increased risk (IR) (>50% of becoming affected) and 27 to be at decreased risk (DR) (< 50% of becoming affected). There was a median period of 9 months between entering the test procedure and receiving a result and the main criticism of the procedure was that it took too long to complete and several individuals experienced considerable anxiety while awaiting their result. One year after receiving their result, almost 40% of individuals had made major life decisions, mainly in the areas of personal relationships, career and financial matters and over a third of fecund individuals in both IR and DR groups had changed their decision about future childbearing. Eighty‐five percent of the IR group and 53% of the DR group requested continued follow up after the 1‐year follow‐up visit. The majority wanted follow up by the genetic clinician, but we have found that in practice many individuals do not attend when offered clinic appointments after this time.