Plasma carnitine ester profile in homozygous and heterozygous OCTN2 deficiency.

The carnitine ester spectrum was studied using ESI tandem mass spectrometry in a 2.5-year-old male Roma child with homozygous deletion of 844C of the SLC22A5 gene, presenting with hepatopathy and cardiomyopathy. Besides the dramatic decrease of plasma free carnitine (1.38 vs 32.7 mumol/L in controls) all plasma carnitine esters were severely decreased in the proband: the total esters were 31.4% of the controls. In three heterozygous siblings the free carnitine level was 62.3% of the normal controls, while the levels of the individual carnitine esters ranged between 15.5% and 163% (average 70.9%). The heterozygous parents exhibited the same pattern. The proband was supplemented with 50 mg/kg per day of L-carnitine oral solution. After 2 months of treatment, his hepatomegaly, elevated transaminases and the pathological cardiac ultrasound parameters normalized. The plasma free carnitine rose to 12.8 mumol/L (39% of the controls). All of the carnitine esters also increased; however, the individual esters were still 8.5-169.7% of the controls (average 55.5%). After 13 months of treatment there was a further increase in free carnitine (15.9 mumol/L) as well as in the level of the individual esters, ranging between 16.1% and 140.3% of the controls (average 66.9%). The data presented here show that, besides the dramatic decrease of free carnitine, the carnitine ester metabolism is also affected in OCTN2 deficiency; the replenishment of the pools under treatment is slow. Despite an impressive clinical improvement, the carnitine metabolism can be still seriously affected.

Excess of malignancies in grandparents of children with malformations? Short communication.

In a prospective study, the occurrence of malignancies in children referred to genetic counseling for congenital malformations, in their sibs, parents and grandparents was registered in 120 families by means of personal interviews. One hundred-and-twenty age matched subjects, admitted for acute respiratory infections or trauma, served as controls. No difference in the occurrence of tumors or leukemias between the two groups was found when the values of patients, sibs, and parents were compared. At the same time, the grandparents of probands with malformations had had significantly more malignancies than the grandparents of the controls. This may be explained by the fact that grandparents lived beyond the age of the usual onset of common cancers and leukemias.

Association of nonsyndromic Wilms tumor with premature centromere division (PCD).

Wilms tumor was discovered in a 22-month-old otherwise healthy girl. Her pretreatment karyotype proved to be normal 46,XX with total premature division (PCD) in 21% of her lymphocyte mitoses. This phenomenon was not seen in the parents. PCD was found in less than 4% of lymphocyte mitoses of five other children with Wilms tumor. The individual finding provides further evidence for a relation of PCD to tumorigenesis; however, elucidation of the question needs further systematic studies.

Increased frequency of the C3*F allele and the Leiden mutation of coagulation factor V in patients with severe coronary heart disease who survived myocardial infarction.

The aim of the present study was to compare the frequencies of the F allele of C3 complement component and the Leiden mutation of coagulation factor V in patients with severe coronary heart disease (CHD) who survived myocardial infarction (MI; group A), and those who had no MI in their case history (group B). We have determined the C3 allele frequencies by electrophoresis, and Leiden mutation by PCR in 338 patients with severe CHD and in 490 and 523 healthy controls, respectively. The C3*F allele frequency was significantly (p = 0.006) higher in group A (0.213) that in group B (0.132). A significant (p = 0.045) difference was found between < or = 60-year group A (0.077) and group B (0.029) patients in the frequency of Leiden mutation. These findings indicate that the C3*F allele and the Leiden mutation may be associated with an increased risk of developing myocardial infarction in CHD patients.

[Centromere separation and malignancy]. / Centromera-szétválás és malignitás.

The centromeres of human chromosomes separate according to a "normal sequence" during mitosis. "Out-of-phase" separation and especially premature centromere division may lead to aneuploidy, and may be regarded as a manifestation of chromosome instability. Evaluation of these phenomena may contribute to a better understanding of predisposition to malignancy and to the possible screening of family members at high risk of cancer. For this reason, a more up-to-date and meticulous research of regulation and clinical significance of centromere separation is warranted.

No evidence of uniparental disomy 2, 6, 14, 16, 20, and 22 as a major cause of intrauterine growth retardation.

Intrauterine growth retardation (IUGR) is defined as length and/or weight below the 10th percentile. Etiology and, consequently, long-term outcome are extremely heterogeneous with chromosomal abnormalities found in up to 7%. Recently, uniparental disomy (UPD), i.e. the inheritance of both homologues of one pair of chromosomes from only one parent, was found in an increasing number of children with IUGR. Particularly, UPD of chromosome 7 was found in up to 10% of patients with IUGR and/or a phenotype of primordial growth retardation or Silver-Russell syndrome (SRS), but also UPD of chromosomes 2, 6, 14, 16, 20, and 22 was reported in single cases with IUGR. To evaluate impact and relevance of UPD in children with IUGR we investigated 23 sporadic cases with IUGR subsequently diagnosed as primordial growth retardation (n = 13) or SRS (n = 10) by molecular methods for UPD of chromosomes 2, 6, 14, 16, 20, and 22. No instance of UPD was found. Inheritance of all chromosomes investigated was biparental in all cases. Therefore, we conclude that UPD of these chromosomes is not a major cause of IUGR.

Trinucleotide repeat polymorphism at five disease loci in mixed Hungarian population.

In apparently healthy, unrelated Hungarians we examined triplet repeat length polymorphism at Huntington disease (HD), spinal and bulbar muscular atrophy (SBMA), spinocerebellar ataxia type 1 (SCA-1), dentatorubral-pallidoluysian atrophy (DRPLA), and myotonic dystrophy (MD) loci. The distribution of alleles of the SCA-1 locus was markedly different compared with Asians and Caucasian samples examined by Watkins WS, Bamshad M, and Jorde LB [1995: Hum Mol Genet 4:1485-1491]. The unimodal distribution of peaks was shifted towards the shorter repeats on the average with 4-5 repeats. Alleles under 21 repeats at the SBMA locus were significantly less frequent in Hungarians than in Asians and Caucasians. We also found significant difference in the distribution of DRPLA allele size at repeat length over 15 repeats; these alleles were less frequent in Hungarians compared with Asians and Caucasians. No significant differences were found in alleles at the MD and also at the HD loci compared with the other groups. These findings suggest that these trinucleotide sites in combination with other markers are particularly useful for determination of the genetic origin of a population, if they can be compared with similar subset of data of other populations. The present results could not confirm the large genetic distance between Hungarian and Oriental races and the relatively short distance between Hungarian and other European populations suggested in earlier reports [Czeizel A, Benkmann H-G, Goedde HW, editors. 1991: Genetics of the Hungarian population. Budapest: Akadémiai Kiadó. p 82-334].

Muscle carnitine acetyltransferase and carnitine deficiency in a case of mitochondrial encephalomyopathy.

Profound decrease of the carnitine acetyltransferase activity (0.08 U/g wet weight; 1.67% of control) and carnitine deficiency (total carnitine was 230 nmol/g wet weight in the patient vs 2730 in the controls) was detected in the skeletal muscle of a female paediatric patient. She died of her illness, which included cerebellar symptoms and slight muscle spasticity affecting mainly the lower extremities, at 1 year of age. Histological examination of the autopsy specimens revealed a selective Purkinje cell degeneration in the cerebellum: the cells had abnormal position, were shrunken and decreased in number, and displayed abnormal dendritic trees and fragmented, disorganized axons. Electron microscopy revealed mitochondrial abnormalities in skeletal and cardiac muscle and also in the Purkinje cells. Deletions of the mitochondrial DNA were detected in the muscle in heteroplasmic form (up to 7%). Mainly the ND4-ND4L region was affected, as evidenced by the PCR; however, other regions of the mitochondrial genome also showed deletions of varying size and extent, suggesting multiple deletions of the mitochondrial DNA.

No latent chromosome damage in oxygen-exposed premature neonates.

The possible effect of in vivo oxygen exposure on chromosomes was examined in lymphocyte cultures of 12 very-low-birthweight infants on the 1st, 8th, and 16th days of intensive care. No increase of cytogenetic anomalies was seen in untreated and bleomycin-treated cultures. The findings suggest that neonatal oxygen exposure is unlikely to cause latent chromosome damage.

No chromosomal instability in offspring of survivors of childhood malignancy.

Chromosomal instability was examined in 20 apparently healthy children of survivors of childhood malignancy. As compared to controls, no increase of spontaneous or bleomycin-induced aberrations (including gaps, breaks, sister chromatid exchanges, pulverization, and premature centromere divisions) were found in these "index children." The results suggest that the offspring of subjects previously receiving chemotherapy and/or radiotherapy for childhood malignancy are probably at no increased risk of latent chromosomal instability.

[Genetic evaluation of mental retardation]. / A mentális retardatio genetikai kivizsgálása.

About 3% of the population is mentally retarded. Due to the progress in medical genetics, congenital origin of disability may be explored in an increasing number of affected children, however, the etiology can still not be determined in a large proportion of the cases, although this would be indispensable for a rational therapy and genetic counselling. This review deals with some general principles and special aspects of genetic evaluation of the mentally retarded.

Excess of mild errors of morphogenesis in childhood lymphoblastic leukemia.

The prevalence of 55 well-defined mild errors of morphogenesis (MEMs) was determined in 100 children with acute lymphoblastic leukemia (ALL), their 80 sibs, 91 mothers, and 76 fathers. Seventy-four patients were treated in Pécs (Hungary) and 26 in Tübingen (Germany). Only white Caucasian index cases were included in the study. Two-hundred children examined for acute infections served as controls. In addition, we analyzed the family history for birth defects and malignancies, associated major malformations, birth weight, birth order, and pretreatment height of the patients. The results of the Pécs and Tübingen patients were at first evaluated separately but since no differences were found only the cumulative data were analyzed further. A significantly increased prevalence of MEMs was found in the ALL patients and their sibs of both sexes: their MEM/subject ratios were 1.59 and 1.51, respectively, whereas the same parameter was 0.74 in the mothers, 0.67 in the fathers and 0.69 in the controls. The same tendency was observed when familial cases and/or age-dependent MEMs were excluded and when malformation-type and variant-type MEMs were evaluated separately. No association of ALL with specific MEMs or combinations was recorded. Family history, associated major malformations, parity and birth weight of the patients did not differ significantly from the local reference values, whereas the pretreatment height of the male probands proved to be greater than expected.

Isolated hypospadias is not associated with signs of midline closure defects.

Ten mild signs of midline closure defect and three anthropometric parameters characterizing the distance of paired organs ("hypertelorism") were investigated in 35 boys with isolated hypospadias and in 70 control children admitted for acute infections. No significant differences between the two groups were obtained. The findings suggest that isolated, nonsyndromic hypospadias is not associated with latent midline closure anomalies.

[Study of offsprings of survivors of childhood malignant diseases]. / Gyermekkori malignus betegségböl gyógyultak utódainak vizsgálata.

Anthropometric, dysmorphologic, and cytogenetic investigations of 21 children of 20 survivors of childhood malignancy revealed no signs of congenital anomalies in any of the subjects examined. No increase of mild errors of morphogenesis (minor anomalies) was observed in the well-developing children; no latent chromosome instability was found in their Bleomycin-treated lymphocyte cultures either. The suggestion that previous oncological therapy does not lead to an increased risk of congenital disorders in the offspring was confirmed by the present findings obtained with various, in part new methods.

Informative morphogenetic variants in patients with schizophrenia and alcohol-dependent patients: beyond the Waldrop Scale.

OBJECTIVE: The authors evaluated the presence or absence of informative morphogenetic variants in patients with schizophrenia compared with alcohol-dependent patients. METHODS: Taking into consideration the criticisms of the Waldrop Scale, which was widely used until recently to define the presence of informative morphogenetic variants, the authors evaluated the presence or absence of 56 informative morphogenetic variants in 50 consecutively admitted patients with schizophrenia and 50 consecutively admitted alcohol-dependent patients. They made a distinction between minor malformations (those developing during organogenesis) and phenogenetic variants (those developing after organogenesis). A kappa index above 75% was considered reliable. RESULTS: Thirty-four of the 56 informative morphogenetic variants met the authors' reliability criterion. Patients with schizophrenia had significantly higher rates of three minor malformations (furrowed tongue, multiple buccal frenula, and hemangioma) and two phenogenetic variants (protruding auricle and large tongue). CONCLUSIONS: The results suggest that using finer distinction in the evaluation of informative morphogenetic variants in schizophrenia may open new perspectives in the research of the neurodevelopmental background of schizophrenia.