Duplication of 14q11.2 associates with short stature and mild mental retardation: a putative relation with quantitative trait loci.
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Aneuploidy↗
Biomedical subjects
Francisco Martínez
Publications and source records attributed to Francisco Martínez.
X-linked infantile spinal muscular atrophy: clinical definition and molecular mapping.
PURPOSE: X-linked infantile spinal-muscular atrophy (XL-SMA) is a rare disorder, which presents with the clinical characteristics of hypotonia, areflexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells and death in infancy. We have previously reported a single family with XL-SMA that mapped to Xp11.3-q11.2. Here we report further clinical description of XL-SMA plus an additional seven unrelated (XL-SMA) families from North America and Europe that show linkage data consistent with the same region. METHODS: We first investigated linkage to the candidate disease gene region using microsatellite repeat markers. We further saturated the candidate disease gene region using polymorphic microsatellite repeat markers and single nucleotide polymorphisms in an effort to narrow the critical region. Two-point and multipoint linkage analysis was performed using the Allegro software package. RESULTS: Linkage analysis of all XL-SMA families displayed linkage consistent with the original XL-SMA region. CONCLUSION: The addition of new families and new markers has narrowed the disease gene interval for a XL-SMA locus between SNP FLJ22843 near marker DXS 8080 and SNP ARHGEF9 which is near DXS7132 (Xp11.3-Xq11.1).
Chromosome Mapping↗
A two base pair deletion in the PQBP1 gene is associated with microphthalmia, microcephaly, and mental retardation.
X-linked mental retardation has been traditionally divided into syndromic (S-XLMR) and non-syndromic forms (NS-XLMR), although the borderlines between these phenotypes begin to vanish and mutations in a single gene, for example PQBP1, can cause S-XLMR as well as NS-XLMR. Here, we report two maternal cousins with an apparently X-linked phenotype of mental retardation (MR), microphthalmia, choroid coloboma, microcephaly, renal hypoplasia, and spastic paraplegia. By multipoint linkage analysis with markers spanning the entire X-chromosome we mapped the disease locus to a 28-Mb interval between Xp11.4 and Xq12, including the BCOR gene. A missense mutation in BCOR was described in a family with Lenz microphthalmia syndrome, a phenotype showing substantial overlapping features with that described in the two cousins. However, no mutation in the BCOR gene was found in both patients. Subsequent mutation analysis of PQBP1, located within the delineated linkage interval in Xp11.23, revealed a 2-bp deletion, c.461_462delAG, that cosegregated with the disease. Notably, the same mutation is associated with the Hamel cerebropalatocardiac syndrome, another form of S-XLMR. Haplotype analysis suggests a germline mosaicism of the 2-bp deletion in the maternal grandmother of both affected individuals. In summary, our findings demonstrate for the first time that mutations in PQBP1 are associated with an S-XLMR phenotype including microphthalmia, thereby further extending the clinical spectrum of phenotypes associated with PQBP1 mutations.
Abnormalities, Multiple↗
A subtelomeric translocation apparently implied in multiple abortions.
PURPOSE: Chromosomal alterations are a major cause of clinically recognized abortions. So cryptic chromosomal rearrangements could be responsible for recurrent miscarriages. METHODS: The study was performed on 18 clinically normal couples who had four or more spontaneous abortions and whose karyotypes were found to be normal. Fluorescence in situ hybridization with specific probes of subtelomeric regions was used after optimizing the amount of probe. RESULTS: Only one subtelomeric translocation was detected between 2p and 3p chromosomes, in a female with seven miscarriages. CONCLUSION: Subtelomeric rearrangements are infrequently related to multiple miscarriages. This kind of studies can be considered specially worthy when a couple have had not only abortions but also offspring with mental and physical anomalies. Thus, possible initial studies should focus on affected children or fetus.
Abortion, Habitual↗
Severe infections after unrelated donor allogeneic hematopoietic stem cell transplantation in adults: comparison of cord blood transplantation with peripheral blood and bone marrow transplantation.
We evaluated the occurrence of severe infections in 192 consecutive adult recipients of volunteer unrelated donor allogeneic hematopoietic stem cell transplants, with a detailed analysis of severe infections after receipt of cord blood transplants (CBTs; n = 48) or bone marrow transplants (BMTs)/peripheral blood stem cell transplants (PBSCTs; n = 144). At a 3-year median follow-up, CBT recipients had a higher risk of developing any severe infection (85% versus 69% in BMT/PBSCT recipients, P < .01). CBT recipients had a higher incidence of severe bacterial infections before day +100, but at 3 years the risks of these and other infections were similar in the CBT and BMT/PBSCT groups. In addition, the 100-day and 3-year incidences of infection-related mortality (IRM) did not differ between groups (P = .2 and .5, respectively). In multivariate analysis, the most significant risk factor for IRM in all 192 patients was monocytopenia (.2 x 10(9)/L). In CBT recipients, only neutropenia (.2 x 10(9)/L) on day +30 and low nucleated cell dose infusion (< 2 x 10(7)/kg) showed a trend for increased IRM (P = .05 in both cases). Stem cell source had no effect on day +100 or 3-year nonrelapse mortality (NRM), cytomegalovirus infection, cytomegalovirus disease (7% versus 6%), or overall survival (36% versus 39%, respectively). The number of mismatches in HLA (A, B, and DRB1) had no effect on any outcome in CBT recipients. In contrast, in the BMT/PBSCT group, the presence of any mismatch by low or high-resolution HLA typing (A, B, C, and DRB1) increased NRM and decreased overall survival (P < .01). IRM was the primary or secondary cause of death in 61% and 59% of CBT and BMT/PBSCT recipients who died, respectively. Our results confirm the relevance of severe infectious complications as source of severe morbidity and NRM after volunteer unrelated donor hematopoietic stem cell transplantation in adults, but suggest that CBT recipients have a similar risk of dying from an infection if an accurate selection of a cord blood unit is done.
Adolescent↗
Evaluation of MLPA for the detection of cryptic subtelomeric rearrangements.
Chromosomal rearrangements involving the telomeres are implied as a significant cause of idiopathic mental retardation. The most frequently used technique to detect these rearrangements was fluorescent in situ hybridization (FISH), an expensive and labor-intensive technique. One of the most promising alternative techniques is multiplex ligation-dependent probe amplification (MLPA). Here, the authors present the evaluation of a double set of probes (the SALSA P036, P019, and P020 human telomere test kits) on a series of 95 patients and 22 normal controls. Overall, 34 patients had been studied by telomeric FISH and MLPA, which was demonstrated to be a reliable method to detect essentially all subtelomeric rearrangements characterized by FISH. In addition, in these 34 patients, 13 dose imbalances were detected by MLPA, but not by FISH analysis. Overall, 12 alterations were observed only with one of the two sets, and they corresponded to polymorphic variants, as they were inherited from healthy parents or also appear in normal controls. The remaining 61 patients were initially studied with SALSA P036, and any putative dose alteration was confirmed with the two other kits and FISH. In the whole series, the authors found 9 dose imbalances evidenced with 2 MLPA kits and confirmed by FISH, representing 10% of patients with subtelomeric rearrangements. On the other hand, one small duplication at 14q11 may be clinically relevant as it appears de novo in one patient. In conclusion, MLPA can be considered a quick, sensitive, cost-effective, and easy method to screen for subtelomeric rearrangements, but any finding based in the testing of one probe should be confirmed by other sources.
Chromosome Deletion↗
Robust, easy, and dose-sensitive methylation test for the diagnosis of Prader-Willi and Angelman syndromes.
We present a new method for differential diagnosis of Prader-Willi (PWS) and Angelman syndromes (AS) that requires only a small amount of DNA including that obtained from amniocentesis specimens. This method not only proved to be robust and rapid, but, most importantly, it can be dosage sensitive, supplying additional information useful for genetic counselling. After methylation-dependent digestion of DNA with HpaII or McrBC, exon 1 of the SNRPN gene is amplified together with a sequence in the CpG island of the H19 gene. Given the similarities in sequence composition and methylation status between the amplified sequences, their co-amplification under semiquantitative conditions allows an easy discrimination between single dosage (present in deletions or chromosomal translocations) and a double-dosage state (uniparental disomy or imprinting error), when the appropriate controls are included. The method we have developed in combination with standard cytogenetic studies and segregation analysis of microsatellite markers offers a rapid and easy procedure to resolve most suspected cases of PWS and AS, and consequently to provide accurate genetic counselling.
Angelman Syndrome↗
Impact of end-stage renal disease care in planned dialysis start and type of renal replacement therapy--a Spanish multicentre experience.
BACKGROUND: Timely referral, preparation and initiation of dialysis remain problematic issues. The purpose of this study is to analyse the effect of chronic renal disease care and education on the mode of dialysis start (planned vs non-planned) and on the modality of renal replacement therapy (RRT). METHODS: A total of 1504 patients from 35 hospitals started RRT in 2003. Out-patient, scheduled initiation of dialysis with a permanent vascular or peritoneal access was considered planned. RESULTS: About 46% of the patients started non-planned dialysis. Of all the patients, 75% had > or =3 months of nephrological follow-up, but nearly half were never educated on dialysis options. Haemodialysis (HD) occurred in 82% and peritoneal dialysis (PD) in 18%. Planned starts were associated (all P < 0.001) with many factors: younger age, longer renal and pre-dialysis follow-up, more education on RRT and general care, more medical visits, more PD (27 vs 8%), more follow-up by specific end-stage renal disease (ESRD) units, more permanent access and better biochemical status at the start of dialysis. Some global differences were found between patients: planned vs non-planned with > or =3 months of follow-up, vs non-planned <3 months follow-up or acute non-planned and <3 months of follow-up or acute patients. HD occurred in a similar rate (92%) in patients with non-planned start, no previous follow-up or who were never educated in dialysis modality options. CONCLUSION: Although a high prevalence of nephrologic care and follow-up was provided among incident patients in dialysis, nearly half the patients did not have a planned dialysis start nor dialysis modality education. Planned start was associated with better analytical and multidisciplinary status. PD was more prevalent in planned starts and when education was given. Specific ESRD units were more likely to provide an optimal care.
Diabetes Mellitus↗
The impact of acute and chronic graft-versus-host disease on normal and malignant B-lymphoid precursors after allogeneic stem cell transplantation for B-lineage acute lymphoblastic leukemia.
BACKGROUND AND OBJECTIVES: The development of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT) for B-lineage acute lymphoblastic leukemia (B-ALL) is associated with a lower probability of leukemia relapse. However, mechanisms by which this GVHD-associated graft-versus-leukemia effect is exerted are poorly understood. In this study, we simultaneously traced the kinetics of normal donor-derived and leukemic recipient-derived B-lymphopoiesis comparing patients with or without GVHD. DESIGN AND METHODS: We used multiparameter flow-cytometry to quantify pro-B (CD19+CD10+CD34+), pre-B (CD19+CD10+CD34-) precursors and malignant lymphoblasts identified by leukemia-associated markers in 161 prospective marrow samples from 39 consecutive B-ALL patients after allogeneic SCT. Chimerism analysis was performed by quantitative real-time polymerase chain reaction of null alleles and insertion/deletion (indel) polymorphisms. RESULTS: Acute GVHD of grades II-IV is associated with a strong inhibition of normal donor-derived pro-B and pre-B precursors at days +30 and +60 post-SCT. Patients who develop chronic GVHD have lower percentages of marrow B-cell precursors during the first year after SCT. Likewise, recipient-derived leukemia B cells were absent at days +30 and +60 in patients with acute GVHD grades II-IV and were less likely to be detected in patients with chronic GVHD. Induction of GVHD as treatment of increasing amounts of leukemia cells causes inhibition of both normal and malignant B compartments even in the absence of steroid therapy. INTERPRETATION AND CONCLUSIONS: We conclude that the development of GVHD after allogeneic SCT is associated with a non-specific inhibition of B-lymphopoiesis.
Acute Disease↗
Wrist arthrography: a simple method.
A technique of wrist arthrography is presented using an adhesive marker-plate with radiopaque coordinates to identify precisely sites for puncture arthrography of the wrist and to obviate the need for fluoroscopic guidance. Radiocarpal joint arthrography was performed successfully in all 24 cases, 14 in the cadaveric wrists and 10 in the live patients. The arthrographic procedure described in this study is simple, safe, and rapid, and has the advantage of precise localisation of the site for puncture without need for fluoroscopic guidance.
Adult↗
Assessment of heavy metal levels in Almendares River sediments--Havana City, Cuba.
The Almendares River watershed covers a large portion of Havana, Cuba and is centrally important to both recreational and other activities in the region. In order to assess current water quality conditions prior to planned remediation efforts, the spatial distribution of six heavy metals and other compounds were determined in river sediments at fifteen sampling stations in the watershed. Metal concentrations in sediments ranged from 86.1 to 708.8 for Zn, 39.3 to 189.0 for Pb, 71.6 to 420.8 for Cu, 84.4 to 209.7 Cr, 1.5 to 23.4 for Co, and 1.0 to 4.3 for Cd microg/g dry weight sediment. Calculated enrichment factors (EF; measured metal versus background mineral conditions) were almost always greater than 1.0, suggesting significant anthropogenic impact on metal levels in the river. The highest EF values were seen immediately below Cotorro (EF>10 for Pb, Cu, and Cd), a suburban town that has an active secondary smelter, and below the largest municipal landfill in Havana (EF>10 for Pb, Cu, Cd, and Zn). Further, three sampling stations had multiple metals at concentrations higher than probable effects concentrations (PEC), implying possible local ecotoxicological impacts. Finally, sequential extractions of the sediments indicated that heavy metals were largely associated with the organic fraction, and it was estimated that up to 62% of metals in the sediments would be susceptible to release back into the water column if hydraulic or other changes occurred in the river. These data are being used to prioritize decisions related to the remediation of the river system.
Cuba↗
There is no evidence that the SDHB gene is involved in neuroblastoma development.
Neuroblastoma and pheochromocytoma have the same embryonal origin. They originate from neural crest cells, and they usually affect suprarenal glands. The SDHB gene encodes the B subunit of succinate dehydrogenase, a protein implicated in the electron transport chain and Krebs cycle. Some mutations have been described in this gene in pheochromocytoma, and this gene could be an appropriate candidate for its study in neuroblastoma given its localization in 1p35-36. The aim of this study was to analyze neuroblastoma tumors in order to assess a possible implication of this gene in neuroblastoma development. We studied 28 neuroblastoma tumor samples from different stages. Mutation research in genomic DNA was carried out after individual amplification of each of the eight SDHB exons by SSCP analysis and sequencing of those samples with migration pattern variants. No variant was found except for three polymorphisms in four neuroblastoma samples. The first polymorphism was a synonymous A-->C change in the third position of codon 6 (exon 1). The other two polymorphisms were a TTC insert at the 5' flanking intron sequence of exon 5 in a stretch of seven TTC repeats. Upon the basis of posterior microsatellite instability and hypermethylation promoter studies, which were not significant, we can conclude that the SDHB gene, a positional candidate gene, is unlikely to be related to either initiation or tumoral progression in neuroblastoma.
DNA Mutational Analysis↗
Analysis of patient flow into dialysis: role of education in choice of dialysis modality.
BACKGROUND: Despite advances in predialysis care, morbidity and mortality remain high. OBJECTIVES: To analyze end-stage renal disease (ESRD) patient demographics and clinical data on education on dialysis treatment options, type of chronic renal replacement therapy (RRT), and effects of planned versus non-planned dialysis start. METHODS: 621 patients, from 24 Spanish hospitals, who started RRT in 2002. Peritoneal or vascular access at dialysis initiation was considered "planned." RESULTS: 304 (49%) patients were non-planned and half of them had prior nephrology follow-up. Of the patients with >3 months nephrology follow-up (76% of all), only half were educated on dialysis modalities. Dialysis education was associated with planned start in 73.4% versus 26% in non-educated patients (p < 0.05), shorter follow-up (55 vs 65 months, p = 0.033), more medical visits in the prior year (6.5 vs 4.4, *p < 0.001), more patients starting peritoneal dialysis (31% vs 8.3%*), and more specific follow-up by ESRD unit versus general nephrology care (63% vs 26%*). Non-planned start was associated with older age (63 vs 60.6 years, p = 0.06), fewer medical visits (4.6 vs 6.4*), less education about modality options, and greater use of hemodialysis (92% vs 75%*). Planned patients had better biochemical parameters at start of dialysis. CONCLUSION: Despite nephrology follow-up, half the patients did not have a planned dialysis start. Planned start was associated with better clinical status. More patients chose peritoneal dialysis when educated about dialysis modality options. ESRD-specific units were more likely to provide patient education.
Aged↗
Localization of MRX82: a new nonsyndromic X-linked mental retardation locus to Xq24-q25 in a Basque family.
Clinical and molecular studies are reported on a Basque family (MRX82) with nonsyndromic X-linked mental retardation (XLMR) in five affected males. A total of 38 microsatellite markers were typed. The XLMR locus has been linked to DXS8067, DXS1001, DXS425, DXS7877, and DXS1183 with a maximum LOD score of 2.4. The haplotype studies and multipoint linkage analysis suggest a localization of the MRX82 locus to an interval of 7.6 Mb defined by markers DXS6805 and DXS7346, in Xq24 and Xq25, respectively. No gene contained in this interval has been so far associated with nonsyndromic mental retardation, except for GRIA3, disrupted by a balanced translocation in a female patient with bipolar affective disorder and mental retardation. However, the search for mutations of this gene did not showed a pathogenic mutation in the present family. Given that there are other eight MRX families overlapping this interval, none of them with known mutation, we conclude that at least one new gene responsible for nonsyndromic mental retardation is located in this region.
Chromosome Mapping↗
Control of Epstein-Barr virus load and lymphoproliferative disease by maintenance of CD8+ T lymphocytes in the T lymphocyte-depleted graft after bone marrow transplantation.
Of 100 bone marrow transplant recipients, 30 (30%) received a CD4(+) lymphocyte-depleted graft (1x10(6) CD8(+) T lymphocytes/kg of body weight). Replication of Epstein-Barr virus (EBV) was observed in 40 patients (40%). The use of a CD4(+) lymphocyte-depleted graft was the only independent risk factor for replication of EBV (relative risk, 11.5; 95% confidence interval, 5.8-22.8; P<.0001). Nevertheless, EBV load in those patients was not higher than in the rest of patients, and the low EBV load prevented the development of lymphoproliferative disease. These results suggest that the presence of CD8(+) T lymphocytes in the bone marrow graft can control EBV load, thereby reducing the risk of developing lymphoproliferative disease.
Antibodies, Viral↗
Screening for microdeletions of the X-chromosome in non-specific mental retardation.
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Chromosome Deletion↗
[Multilocular cystic nephroma. A diagnostic and therapeutic challenge. Report of two cases].
OBJECTIVES: Multilocular cystic nephroma is a rare benign entity grouped among the cystic non genetic diseases, which usually presents with a clinical picture and radiological features indistinguishable from malignant neoplasias, making impossible to rule out malignancy preoperatively. METHODS: We report two cases of multilocular cystic nephroma which were treated with different surgical attitudes despite their clinical and radiological similarities, because on the second case intraoperative pathologic study of the specimen was performed. RESULTS: The diagnosis of multilocular cystic nephroma was confirmed in both cases, with the difference that radical nephrectomy was performed in the first case whereas the intraoperative study of the tumor in the second allowed to perform tumorectomy with renal parenchyma preservation. CONCLUSIONS: We consider that in the presence of a multiloculated renal mass of complex appearance and benign clinical behavior, the intraoperative study of the tumor will avoid performance of radical surgery.
Female↗
A submicroscopic deletion of 11p13 associated with the WAGR syndrome.
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Chromosomes, Human, Pair 11↗