High prevalence of short-chain acyl-CoA dehydrogenase deficiency in the Netherlands, but no association with epilepsy of unknown origin in childhood.

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of metabolism, most frequently associated with developmental delay and/or epilepsy. Most SCADD patients carry common SCAD-encoding gene ( ACADS) variants or these variants in combination with a rare ACADS mutation, in the Netherlands predominantly the c.1058C>T. Epilepsy in childhood often remains unexplained and patients with epilepsy related to SCADD may remain undiagnosed because studies for SCADD are often not performed. To test this hypothesis and to further estimate the extent of the Dutch SCADD population, we performed a study on blood spot samples in 131 paediatric patients with epilepsy and 909 anonymous newborns and investigated the presence of the 2 common ACADS variants and the rare c.1058C>T mutation. Overall, the 2 common ACADS variants and the rare c.1058C>T mutation were detected in either homozygous or compound heterozygous forms in 9.2% of the epilepsy and 7.5% of the reference group. A birth prevalence of SCADD with a mutation/variant genotype in the Netherlands as high as >1:1,000 was calculated. This is in contrast with the low number of patients diagnosed clinically and supports the hypothesis that SCADD is clinically irrelevant. Furthermore our study does not support an association between SCADD and epilepsy.

Potential efficacy of enzyme replacement and substrate reduction therapy in three siblings with Gaucher disease type III.

We report three siblings with Gaucher disease type III, born between 1992 and 2004. During this period, new developments resulted in different potential therapies, changing clinical practice. The two eldest siblings received enzyme replacement therapy (ERT) from the age of 24 and 5 months respectively, later followed by an increase in dosage. ERT was combined with substrate reduction therapy (SRT) from the ages of 12 and 8 years, respectively. In the youngest sibling the combination of high-dose ERT and SRT was given from the age of 5 months. The two eldest siblings showed significant neurological impairment from the age of 1.5 years, starting with a convergent strabismus and partial oculomotor apraxia, followed by cognitive decline and an abnormal EEG and BAER. In contrast, the neurological development in the youngest sibling is almost completely normal. At the age of 3 years, cognitive development, EEG and BAER are all normal. Disturbed saccadic eye movements, which were already present at the start of therapy, remained stable. In addition to the clinical efficacy, we report on the biochemical response to therapy. Based on our results, the combination of high-dose ERT and SRT should be considered as a possible therapeutic approach for GD III, especially if started at a young age. Further follow-up studies are necessary to explore the long-term therapeutic effects.

[Short-chain acyl-CoA dehydrogenase deficiency (SCADD): relatively high prevalence in the Netherlands and strongly variable fenotype; neonatal screening not indicated]. / De vetzuuroxidatiestoornis 'short chain'-acyl-CoA-dehydrogenase- deficiëntie: relatief hoge prevalentie en sterk wisselend fenotype; neonatale screening niet geïndiceerd.

OBJECTIVE: To describe the clinical, genetic, and biochemical characteristics of short-chain acyl-CoA dehydrogenase deficiency (SCADD), a clinically heterogeneous metabolic disorder for which neonates are screened for in parts of the United States and Australia. To explore the genotype-phenotype relation and to discuss neonatal screening for SCADD. DESIGN: Retrospective study of 31 Dutch SCADD patients and 8 SCADD relatives. METHOD: Patients and relatives were included ifbiochemical SCADD characteristics (increased C4-carnitine and/or ethylmalonic acid) were present in combination with a mutation and/or the c.511C>T or c.625G>A variant on each SCAD-encoding (ACADS) allele. The patients were subdivided into 3 genotype groups: mutation/mutation, mutation/variant and variant/variant group. RESULTS: A birth prevalence for SCADD of at least 1:50,000 was calculated. Most patients presented before the age of 3 years, mainly with developmental delay, epilepsy, behavioural disturbances and/or hypoglycaemia. The ACADS genotype showed a statistically significant association with biochemical, but not with clinical characteristics. In total 7 out of 8 SCADD relatives were free of symptoms. In 5 of the 31 patients, of whom 2 had severe symptoms, a second diagnosis was made which might explain the symptoms. CONCLUSION: SCADD was far more common than had previously been assumed and clinical symptoms in SCADD were non-specific, often transient or absent and not correlated with specific ACADS genotypes. SCADD does not meet major neonatal screening criteria and is therefore not suited for inclusion in neonatal screening programmes.

[Lactic acidosis and accumulation of glutamate in the blood of neonates following treatment with calcium levulinate for hypocalcaemia]. / Lactaatacidose en glutamaatophoping in het bloed van neonaten na behandeling met calciumlevulaat wegens hypocalciëmie.

The data from 5 clinics concerning 8 infants, who had developed severe lactic acidosis and hyperglutamic acidaemia were reviewed. Blood-lactate levels were up to 15 mmol/l (reference level: < 2) and plasma-glutamate levels up to 1632 pmol/l (reference level: 14-78), and there was no concomitant hyperglutaminaemia (levels up to 1032 micromol/l (reference level: 333-809)). A positive correlation between the amount of calcium levulinate administered and the degree of hyperglutamic acidaemia was found. Replacement of the calcium levulinate by another calcium salt caused a reversal of the biochemical abnormalities of the patients. Two of the infants had a 22q11 microdeletion. This development of severe acidosis in infants who had been given a calcium supplement in the form of calcium levulinate may be related to genetic predisposition. The paradoxal hyperketonaemia and generalized aminoaciduria in 4 other patients suggested disturbed function ofthe mitochondrial respiratory chain. The hypothesis of the occurrence of an underlying defect of the mitochondrial respiratory chain was tested in the muscle tissue of one 22q11 patient, but this showed no abnormalities. Excessive accumulation of glutamate because of dysfunction ofglutamine synthetase, which forms glutamate from glutamine seems unlikely because of the relatively low values of plasma glutamate compared to the glutamine plasma levels. Calcium levulinate should no longer be used in neonates as it may lead to lactic acidosis.

Analysis of pyrimidine synthesis de novo intermediates in urine during crisis of a patient with ornithine transcarbamylase deficiency.

Analysis of pyrimidine synthesis de novo intermediates and pyrimidine degradation products in urine samples from a decompensated patient with an ornithine transcarbamylase deficiency showed a strikingly aberrant metabolic profile. Strongly elevated levels of N-carbamyl-aspartate, orotate and uracil were present whereas the concentration of uridine was only marginally increased. The level of pyrimidine excretion appeared to be independent of the ammonia levels in blood, which were only mildly increased.

The 625G>A SCAD gene variant is common but not associated with increased C4-carnitine in newborn blood spots.

The 625G>A variant of the short-chain acyl-CoA dehydrogenase (SCAD) gene is considered to confer susceptibility for developing 'clinical SCAD deficiency' and appears to be common in the general population. To determine the frequency of the 625G>A variant in The Netherlands, we analysed 1036 screening cards of 5- to 8-day-old newborns and found 5.5% homozygous and 31.3% heterozygous for the 625G>A variant. An increased blood/plasma C4-carnitine concentration is considered to be one of the biochemical characteristics of SCAD deficiency. To explore the correlation of C4-carnitine levels with the 625G>A variant, we determined the C4-carnitine concentration, as well as the ratio of C4- to free carnitine, in blood spots from newborns, who were detected as homozygous, heterozygous or noncarriers for the gene variant. No significant differences were found between these groups. Our study demonstrates a high frequency of the 625G>A SCAD gene variant in the Dutch population, but no correlation to significantly increased C4-carnitine levels in blood spots taken between the 5th and 8th days of life. This latter observation might be the result of the relatively late timing of neonatal screening in our country, implying that fatty acid oxidation disorders may be missed at that stage. If the 625G>A variant is associated with clinical SCAD deficiency, the high frequency of the variant suggests a possible involvement of SCAD deficiency in the pathogenesis of common disorders, probably in relation to other genetic and/or environmental factors. However, homozygosity for the 625G>A variant might be only a biochemical phenomenon, representing a 'nondisease'.

[Effects of articles published in the Dutch Journal of Medicine]. / Effecten van artikelen gepubliceerd in het Nederlands Tijdschrift voor Geneeskunde.

OBJECTIVE: To inventory the effects of publishing in the NTvG. DESIGN: Retrospective, descriptive. METHODS: The first authors of the articles of the sections Clinical lessons, Capita selecta, For practice, Original articles, Case reports and Side effects of drugs, from the issues 27-53 of Volume 138 (1994) of the NTvG were approached for a written enquiry about the effects of their articles. Reactions in the form of letters to the editor were assessed by screening the relevant section. RESULTS: The results of the enquiry concerned 165 articles. The authors of 160 articles (97%) reported that they had been approached in person with reference to the publication, on average 15.7 times orally and 2.0 times in writing. The authors of 66 articles (40%) were invited to deliver a lecture, data from 62 articles (38%) were used by others and 54 articles (33%) resulted in (continuation) research. An approach by the media followed after 23 articles (14%). A positive effect on the number of relevant patient referrals was mentioned of 4 (44%) articles from section For practice and 7 (30%) articles from section Clinical lessons. Various other effects were reported of 48 articles (29%). Forty (20%) of the total of 197 articles involved in the study were followed by one or two letters to the editor, prompted mostly by Clinical lessons (33%). CONCLUSION: Virtually all articles produced an effect. Many articles were followed by personal reactions and many articles elicited a response indicating influence on medical teaching, science or clinical activity.

[Influence of specific clinical lessons in the Dutch Journal of Medicine on clinical management]. / Invloed van enkele klinische lessen in het Nederlands Tijdschrift voor Geneeskunde op het klinisch handelen.

OBJECTIVE: To establish whether publication of an article propagating a laboratory test leads to measurable increase of the number of requests for that test. DESIGN: Retrospective. METHOD: From volume 138 (1994) of the Dutch Journal of Medicine (NTvG), three clinical lessons were selected that contained an unequivocal clinical message and a recommendation to request a specific laboratory test for particular patients. All laboratories performing the test in question were asked to report the number of requests per month in the months before, after and during publication of the article in question and during the same months of 1993. The difference between the number of requests in the period after publication of the article in 1994 and in the same period in 1993 was determined and tested postulating a Poisson distribution. RESULTS: Regarding two clinical lessons (one about determination of Coxsackie virus in neonates and one about examining arthritis patients for parvovirus B19) no significant difference in the numbers of requests before and after the publication was found, particularly also because the laboratories could not supply itemized data so that relevant information was lost in a flood of other data. The third clinical lesson (about determination of antibodies against Onchocerca in patients complaining of itching after a trip to the tropics) was followed by a significant increase of the number of requests (from 50 to 90; p < 0.001) in the 3 months following publication. CONCLUSION: Publication of a clinical lesson about a recommended laboratory test for onchocerciasis in the NTvG resulted in a significant rise of the number of requests for that test.

[Reports in the Dutch newspapers prompted by articles from medical scientific journals]. / Berichten in Nederlandse nationale kranten naar aanleiding van artikelen uit medisch-wetenschappelijke tijdschriften.

OBJECTIVE: To gain an impression of the frequency and nature of reports in Dutch newspapers about publications in medical-scientific journals. DESIGN: Retrospective, descriptive. METHODS: Press reports appearing during February to July 1995 in the internal and external collections of newspaper cuttings of the Ministry of Public Health, Welfare and Sports, both composed of reports from, among other things, nine popular evening and morning newspapers, were examined for articles that had been prompted directly by medical publications; this study was carried out in the editorial offices of the Dutch Journal of Medicine (NTvG). The title of the publication and the report, the name of the newspaper and the name of the journal were recorded. RESULTS: In all, 34 reports prompted by 27 different articles were found, most of them (21%) written in reference to publications in The New England Journal of Medicine, followed by the NTvG (15%). The list was headed by socially relevant subjects such as cancer and aids (29% and 12%, respectively, of the reports). The Telegraaf and the Volkskrant contained the largest numbers of reports (both 18%) and nearly all newspapers used journals published in either English or Dutch. CONCLUSION: Dutch newspapers regularly use articles from various medical-scientific journals published in English and in Dutch as a direct source for reporting. Most attention was given to socially relevant subjects such as cancer and aids.