Epilepsy in ring 14 syndrome: a clinical and EEG study of 22 patients.

PURPOSE: To characterize epileptic phenotype, electroencephalography (EEG) features, and epileptic evolution in patients with ring 14 r(14) syndrome. METHODS: Twenty-two patients with ring chromosome 14 were enrolled in the study. We examined age at onset, seizure semiology and frequency at onset and at follow-up, drug responsiveness/resistance, and interictal/ictal EEG data. The degree of severity of the epileptic phenotype negatively influences child cognitive development. KEY FINDINGS: The incidence of epilepsy in patients with r(14) syndrome is virtually 100%, characterized by early onset, polymorphic seizures, and drug-resistant seizures. In addition, we ascertained focal secondarily generalized epilepsy, seizure cluster tendency, frequent status epilepticus, and a rather typical epilepsy evolution. EEG abnormalities consisted of slow background activity with pseudoperiodic bursts of generalized slow waves in the early stage, focal frontotemporal or temporoposterior slow waves with multifocal spikes interposed, and unusual rhythmic fast recruiting posterior spikes followed by secondary generalization. The degree of severity of the epileptic phenotype negatively influences child cognitive development. SIGNIFICANCE: This study provides a more precise definition of seizure types, natural history, and drug responsiveness of r(14) syndrome, a highly epileptogenic chromosomal condition.

Epilepsy in ring 14 chromosome syndrome.

Ring chromosome 14 [r(14)] is a rare disorder. The aim of this study was to describe two new cases of r(14) drug-resistant epilepsy, and, through an extensive review of literature, highlight those epileptological features which are more commonly found and which may help in early diagnosis, genetic counseling, and treatment. Epilepsy onset in r(14) syndrome takes place during the first year of life; seizures are generalized or focal and less frequently myoclonic. Seizures might be induced by fever. Focal seizures are characterized by staring, eye or head deviation, respiratory arrest, swallowing, and hypertonia/hypotonia or clonic movements. Ictal EEG might show both focal and diffuse discharges. Interictal EEG reveals mainly focal abnormalities. Mental retardation represents a constant feature. Neurological assessment yields a delay in motor skill acquisition and less frequently both pyramidal and cerebellar signs. Dysmorphic features are evident in the majority of cases. Epilepsy associated with r(14) has many features that entail a challenging diagnostic process. The reported cases of r(14)-related epilepsy seem to highlight a series of common elements which may be helpful in pointing the clinician towards a correct diagnosis.

Id4 is deregulated by a t(6;14)(p22;q32) chromosomal translocation in a B-cell lineage acute lymphoblastic leukemia.

BACKGROUND AND OBJECTIVES: Chromosome translocations resulting in gene overexpression are commonly associated with lymphoid neoplasia. Enhancer elements of the immunoglobulin or T-cell receptor (TCR) loci are abnormally located in the vicinity of the entire coding sequences of genes which exert an influence on the normal maturation and differentiation program of lymphoid cells. DESIGN AND METHODS: A patient who presented with a B-cell lineage acute lymphoblastic leukemia had a t(6;14)(p22;q32). Cytogenetic and molecular findings confirmed the involvement of IgH. Molecular cloning of the breakpoint revealed that this was located near the coding sequence of the Id4 gene, a helix-loop-helix (HLH) inhibitor protein. Alu-repeated sequences at the 6p22 end flanked a short stretch of 10 bases shared by the 6p22 and 14q32 ends, suggesting that a deletion or a looping-Alu mediated mispairing mechanism may lead to this chromosome translocation. RESULTS: Northern blot and real-time polymerase chain reaction analyses showed that the Id4 mRNA was abnormally overexpressed in this case. Only the two smaller Id4 mRNA products were detected (1.6 and 1.1 kb). Immunohistochemical analysis of Id4 protein was also assayed in a series of hematologic malignancies. Marked overexpression was found in two cases of T-cell prolymphocytic leukemias and in four B-cell lineage acute lymphoblastic leukemia including one case with the t(8;14) and another case with a p53 mutation. INTERPRETATION AND CONCLUSIONS: The Id4 gene may behave as an oncogene in some human leukemias, perhaps through its capacity to sequester specific B-cell transcription factors. A genetic recombination between Alu-repeated sequences may not be the exclusive mechanism of generating pathogenic chromosomal translocations.

Genetic analysis of the cellular oncogene fos in patients with chromosome 14 encoded Alzheimer's disease.

A major gene for familial early-onset Alzheimer's disease (AD) has been localised to chromosome 14q24.3. The c-fos gene (FOS), localised to 14q24.3-q31, is a candidate for the AD gene since it may be involved in the transcription regulation of the amyloid precursor protein gene (APP). Part of APP codes for the beta A4 amyloid present in AD brain lesions. We analyzed linkage of AD in the 2 early-onset AD families. AD/A and AD/B, using a polymerase chain reaction (PCR) based assay for a restriction fragment length polymorphism (RFLP). The RFLP is detected in BstNI digested DNA and is located near the 3' end of FOS. No obligate recombinants were detected. The 4 exons of FOS were sequenced in one pathologically confirmed AD patient in each family. No exonic mutations were found. Two intronic sequence variations were observed, one in intron 2 and one in intron 3. The intron 2 variation did not segregate with AD. The intron 3 variation which is a single G insertion was used in linkage studies in families AD/A and AD/B and showed conclusive linkage in both families in the absence of recombinants. Therefore, FOS cannot yet be excluded as a candidate gene for AD in these families since mutations may be present in regulatory sequences.

Cromosoma 14 en anillo / Ring chromosome 14

Se describen las características clínicas y de laboratorio de una niña con dismorfia cráneofacial, retardo psicomotor, epilepsia, síndrome neurológico, unido a malformaciones menores y mayores, lo que hace sospechar la presencia una alteración cromosómica. El estudio de su cariotipo en sangre periférica, reveló la existencia de un anillo cromosómico derivado de un cromosoma 14

Characterization of translocation t(1;14)(p32;q11) in a T and in a B acute leukemia.

The TAL1 locus on chromosome band 1p32 is rearranged in 15 to 29% of human T-cell acute lymphoblastic leukemias (T-ALLs). These alterations consist of either a tald submicroscopic deletion (12-26% of T-ALL) or a t(1;14)(p32;q11) chromosomal translocation (3% of childhood T-ALL). Both types of alterations preferentially affect the 5' part of the TAL1 locus. Their main consequence appears to be transcriptional activation of the TAL1 gene. We have characterized two cases of t(1;14)(p32;q11) in ALL. Both affect the TCR delta gene segments at 14q11 and the 5' part of the TAL1 locus at 1p32. The first case represented a 'classical' t(1;14), associated with T-ALL. Its analysis indicates the use of a recombination signal-like sequence localized in the third exon of TAL1 in the translocation process. In the other case, the rearrangement to the D delta region occurred 5' to the TAL1 transcription start sites. This case exhibited a B-lymphoid immunophenotype thus suggesting that the putative oncogenicity of TAL1 activation is not restricted to T-cell malignancies.

Molecular analysis of T-cell receptor transcripts in a human T-cell leukemia bearing a t(1;14) and an inv(7); cell surface expression of a TCR-beta chain in the absence of alpha chain.

The polymerase chain reaction (PCR) was used to amplify cDNA in order to characterize normal and hybrid T-cell receptor (TCR) gene rearrangements derived from a T-cell acute lymphoblastic leukemia (T-ALL) bearing a chromosome 7 inversion. The nucleotide sequence analysis of the amplified product showed the presence of an out-of-frame V beta/J gamma/C gamma transcript and an in-frame V gamma/J gamma/C beta transcript which result from an interlocus recombination between the TCR-beta and gamma loci and the transcription of the reciprocal hybrid TCR gene. The sequence analysis of the reciprocal DNA segment directly involved in the breakpoint of the inversion showed a recombination between a J gamma-sequence heptamer signal and a coding J beta gene segment. The exonuclease nibbling of each DNA extremity and the non-templated nucleotide insertion observed at both coding and reciprocal joints demonstrate that the inversion is mediated by the lymphocyte recombinase complex. During T-cell differentiation, TCR-beta genes are rearranged prior to TCR-alpha genes. In the present case of T-ALL, we have shown that TCR-delta genes are rearranged at both loci, excluding productive rearrangements of TCR-alpha genes. The molecular analysis of the normal TCR genes derived from the leukemic cells revealed the presence of productively rearranged TCR-beta, gamma, and delta genes. Cell surface staining of these cells showed the presence of CD3 molecules and of a TCR-beta chain corresponding to the normal beta allele expressed in a disulfide-linked complex with a protein which is not TCR-alpha, gamma, or delta. This could represent the cell surface expression of the hybrid TCR-V gamma/C beta protein or the expression of a TCR-beta homodimer.

Síndrome de Down portador de una inversión pericéntrica del cromosoma 14 / Down's syndrome carrying a pericentric inversion of chromosome 14

El propósito del presente trabajo es el de describir a un paciente masculino con el síndrome de Down, quien al realizarle los estudios cromosómicos en cultivo de linfocitos de sangre periférica y con técnicas de bandas G, mostró un complemento cromosómico de 47,XY+21 y una inversión pericéntrica del cromosoma 14 con sus puntos de ruptura en las bandas pll y q22. El padre y el hermano presentaron cariotipo normal I, la madre fue portadora de la inversión. Se discuten los mecanismos probables del origen de ambas anomalías y los casos reportados en la literatura

Recombinations of chromosomal bands 6p21 and 14q24 characterise pulmonary hamartomas.

Cytogenetic analysis of short-term cultures from seven pulmonary hamartomas revealed an abnormal karyotype in six of them. The most characteristic aberration was an exchange of material between 6p21 and 14q24, found in three tumours. Abnormalities of either 6p or 14q were seen in another two hamartomas. Other regions that were rearranged more than once were 12q (three times) and 17p (twice), sometimes in exchange with 6p or 14q and giving rise to complex derivative chromosomes. Only one tumour had aberrations that did not involve 6p, 12q, 14q, or 17p. These results-together with the data on three previously reported pulmonary hamartomas, two of which also had t(6;14)-show that recombinations between 6p21 and 14q24 are common, and hence probably pathogenetically important. The data support the view that these tumours are genuine neoplasms rather than developmental anomalies. The coexistence of a common 14q24 breakpoint in uterine leiomyomas and pulmonary hamartomas indicates that a gene important in the genesis of both tumours exists in this band.

Chromosomal abnormalities in patients with Hodgkin's disease: evidence for frequent involvement of the 14q chromosomal region but infrequent bcl-2 gene rearrangement in Reed-Sternberg cells.

BACKGROUND: Rearrangements of the bcl-2 gene (also known as BCL2) have been detected in up to 40% of cases of Hodgkin's disease, and it has been speculated that such rearrangements may have a role in the pathogenesis of Hodgkin's disease. PURPOSE: The purposes of this study were (a) to assess the frequency of clonal chromosomal abnormalities in Hodgkin's disease, (b) to identify recurrent changes, (c) to determine whether the bcl-2 gene rearrangement was present in Reed-Sternberg cells (the neoplastic cells of Hodgkin's disease) and their variants, and (d) to analyze whether the presence of t(14;18) translocations in Reed-Sternberg cells explains the observed bcl-2 gene rearrangements in Hodgkin's disease. METHODS: A cytogenetic study was performed on biopsy specimens from 28 consecutive untreated patients with Hodgkin's disease. The same patients were analyzed for bcl-2 gene rearrangement by a polymerase chain reaction (PCR) technique. To ascertain whether the abnormal karyotypes were present in and restricted to Reed-Sternberg cells, we also performed in situ hybridization with chromosome-specific probes. RESULTS: Abnormal metaphases were identified in 23 of the 28 patients. In 11 patients, the chromosome 14q region was abnormal; in six of these patients, there was involvement of the 14q32 region that comprises the gene encoding for heavy-chain immunoglobulin. Only one patient had a t(14;18) translocation, whereas almost 40% of these 28 patients showed bcl-2 gene rearrangements by a PCR method. The in situ hybridization method showed that the abnormal karyotype was present in and restricted to Reed-Sternberg cells. CONCLUSIONS: We conclude that the majority of cases of Hodgkin's disease contain a clonal population with an abnormal karyotype, comprising the Reed-Sternberg cells. The q32 region of chromosome 14 is frequently involved, but a t(14;18) translocation is extremely infrequent. The occurrence of a bcl-2 gene rearrangement in Hodgkin's disease most likely results from the presence of sporadic, small bystander B lymphocytes that carry the translocation and that also can be frequently detected in reactive lymphoid tissue such as tonsils. Also, a range of different chromosomal translocations may provide growth or survival advantages to Reed-Sternberg cells.

The detection of specific gene rearrangements in non-Hodgkin's lymphoma using the polymerase chain reaction.

Characteristic gene rearrangements are present in most non-Hodgkin's lymphomas (NHL). These are usually detected by Southern blotting techniques. In this study, the ability of the polymerase chain reaction (PCR) to detect the t(14;18) chromosomal translocation and immunoglobulin heavy chain (IgH) gene rearrangement was evaluated. DNA from 14 follicular and 42 diffuse B-cell lymphomas was examined using oligonucleotide primers specific for opposing sides of the IgH gene rearrangement on chromosome 14 (towards conserved VH and JH sequences) and opposing sides of the t(14;18) chromosomal translocation (towards the major breakpoint region of the bcl-2 gene on chromosome 18 and conserved JH sequence on chromosome 14). The t(14;18) translocation was detected in 57% of follicular lymphomas and 21% of diffuse B-cell lymphomas. Clonal IgH gene rearrangements using PCR were detected in 50% follicular and 52% of the diffuse lymphomas. Either or both of these rearrangements were detected in 93% follicular and in 59% of diffuse lymphomas. PCR is a rapid and easy technique that can detect the abnormal rearrangement of the bcl-2 gene and clonal IgH rearrangement, indicating the presence of lymphoma. This may be of benefit in monitoring response to therapy and in predicting prognosis in this disease.

Clonal rearrangement of chromosome band 6p21 in the mesenchymal component of pulmonary chondroid hamartoma.

Pulmonary chondroid hamartomas (PCH) are biphasic benign tumors that contain both mesenchymal and epithelial populations. In this report we describe two PCH in which clonal translocations at chromosome band 6p21 were demonstrated in mesenchymal cells. One of these had a unique translocation, t(6;14)(p21;q24), that was also found in one of two PCH karyotyped previously. The t(6;14) has not been described in other varieties of benign or malignant neoplasia. The 6p21 aberrations are of particular interest because break points in this chromosomal region appear to be characteristic of endometrial polyps. Endometrial polyps, like PCH, are biphasic benign tumors in which mesenchymal clonality has been demonstrated.

Cytogenetics in multiple myeloma and plasma cell leukemia: simultaneous cytogenetic and cytologic studies in 51 patients.

Cytogenetic studies in patients with multiple myeloma (MM) and plasma cell leukemia (PCL) have in general been largely unsuccessful. The investigation of mitoses of nonmalignant hematopoietic precursor cells, rather than mitoses of malignant plasma cells might account for the low percentage of pathological genetic findings. We investigated bone marrow (BM) cells of 51 patients both cytogenetically and cytologically. In patients with a normal karyotype (n = 39) nearly all mitoses examined cytologically (107/117) derived from granulopoietic or erythropoietic cell lineages. In contrast, 20/27 metaphases in patients with a pathological karyotype (n = 12) were found to be plasma cell mitoses. These findings may explain the low rate of chromosomal rearrangements in MM and may suggest that the real abnormality rate is considerably higher.

No evidence for linkage of familial hypertrophic cardiomyopathy and chromosome 14q1 locus D14S26 in a Chinese family: evidence for genetic heterogeneity.

To understand the molecular basis of familial hypertrophic cardiomyopathy (FHC) in the Chinese population, a family with FHC was investigated. Nineteen family members who were 16 years of age or older were examined by M-mode or two-dimensional echocardiography. Eight members were diagnosed to be affected echocardiographically or clinically. Lymphocytes isolated from 20 family members were successfully transformed into permanent lymphoblastoid cell lines by Epstein-Barr virus. Three genomic DNA probes (CRI-L436, CRI-L329, and pSC14) that were derived from chromosome 14q1 loci and demonstrated to be linked closely to FHC were used to probe this family. Using the techniques of restriction fragment length polymorphism (RFLP) and linkage analysis, the probe CRI-L436, which recognized locus D14S26, was found informative in this family. The lod scores were -2.0 at theta = 0.025 and -1.49 at theta = 0.05. Thus, there was no evidence of linkage between the locus D14S26 and the gene for FHC in the pedigree studied. In addition, polymerase chain reaction (PCR) amplification did not indicate a mutation on exon 13 of the beta cardiac myosin heavy chain gene as previously reported. Our data suggest that FHC is a genetically heterogeneous disease.

Polymorphisms of candidate genes in essential hypertension.

1. Family and population studies have reported that blood pressure has a heritability of 30-50%, but simple genetic models do not readily explain the patterns of inheritance of hypertension. 2. Restriction fragment length polymorphisms were used to study allele frequencies of a selection of candidate genes that may be important in determining the genetic component of hypertension. These included the genes for renin, haptoglobin, neuropeptide Y and cardiac myosin beta heavy chain. 3. There was no significant association between alleles at any of these loci and the presence of hypertension in this population, suggesting that the contribution of variation at these loci to the genetic component of the variance in hypertension may be quite small.

The significance of circulating cells carrying t(14;18) in long remission from follicular lymphoma.

Peripheral blood mononuclear cell fractions from 15 patients in continuous clinical remission from follicular lymphoma for longer than 10 years were examined for cells carrying the t(14;18) translocation using the polymerase chain reaction (PCR). The assay used was able to detect one positive cell in approximately 5 x 10(5) cells (a single 14q+ molecule in 2.5 micrograms DNA). Cells positive for t(14;18) were found in six of eight patients initially presenting with stage III or IV disease, compared with zero of seven of those with stage I or II disease (P less than .05). In two cases 14q+ junction regions were also successfully amplified from formalin-fixed biopsy material obtained at presentation 12 and 17 years previously. In both, sequence analysis demonstrated that the cells circulating in remission belonged to the original clone. These results indicate that cells bearing t(14;18) frequently persist in the peripheral blood in long remission of advanced follicular lymphoma and question the value of their presence as a predictor of relapse.