Ana-Rebeca Jaloma - Academia.edu (original) (raw)
Papers by Ana-Rebeca Jaloma
Various inherited bleeding disorders deserve careful medical management due to their implications... more Various inherited bleeding disorders deserve careful medical management due to their implications in women's health. In both hemophilia A and B, almost exclusively, males are affected while carrier females are generally asymptomatic. Nevertheless, carriers may present important bleeding tendencies, which can eventually constitute a serious threat to life, especially after surgery or postpartum. In addition, in rare but significant cases, some genetic mechanisms have been found to cause hemophilia in females. Aside from von Willebrand disease, which is the most widespread and better described hemorrhagic condition in women, platelet disorders and some rare clotting deficiencies cause a wide variety of mucocutaneous bleedings, menorrhagia, or postpartum bleeding, hence constituting an important health risk. A review of the genetic and pathophysiological aspects as well as main clinical complications of all these conditions will allow for preventive practices aimed at improving the quality of life of women with bleeding disorders.
Blood Cells Molecules and Diseases, Jul 1, 2020
INTRODUCTION Molecular analysis in haemophilia is currently used in the diagnosis, treatment and ... more INTRODUCTION Molecular analysis in haemophilia is currently used in the diagnosis, treatment and prognosis of this disease. Hispanic populations in Latin America have been of interest to researchers due to the reportedly high prevalence of inhibitors in these patients. AIM To perform next-generation sequencing (NGS) in a cohort of Mexican patients with HA and HB and correlate with clinical phenotypes. METHODS Patients with Haemophilia A (HA) or haemophilia B (HB), were evaluated using NGS with an Ion AmpliSeq Custom Panel. Odds ratios (ORs) for associations between F8 variants and inhibitors were obtained. RESULTS A total of 85 patients (60 with HA and 25 with HB) were included. Pathogenic variants in F8 were found in 93.3% of HA patients and in F9 in 96% of HB patients. Twelve novel potentially pathogenic variants were found. Inhibitors were observed in 20% of patients with severe HA. Four patients clinically diagnosed with HA were negative for F8 variants. CONCLUSION Overall detection rate of pathogenic variants in F8 and F9 genes was 94.6%. We identified 12 non previously reported variants and pathogenic variants in other coagulation related genes. Molecular diagnosis of HA and HB permits better options for management, assessment and genetic counseling.
Taiwanese Journal of Obstetrics and Gynecology, 2016
Objective: We report on two rare Xq rearrangements, namely a t(X;9)(q24;q12) found in a mildly-af... more Objective: We report on two rare Xq rearrangements, namely a t(X;9)(q24;q12) found in a mildly-affected girl (Patient 1) and a rea(X)dup q concomitant with a rob(14;21)mat in a Down syndrome girl (Patient 2). Case report: Both rearrangements were characterized by banding techniques [Giemsa (G), constitutive heterochromatin (C), and bromodeoxyuridine (BrdU) pulse], fluorescence in situ hybridization (FISH) assays, human androgen receptor (HUMAR) assays, and microarray analyses. Patient 1 had a t(X;9)(q24;q12)dn. Patient 2 had a de novo rea(X)(qter/q23 or q24::p11.2/qter) concomitant with an unbalanced rob(14;21)mat. X-Inactivation studies in metaphases and DNA revealed a fully skewed inactivation: the normal homolog was silenced in Patient 1 and the rea(X) in Patient 2. Both rearranged X chromosomes were of paternal descent. Microarray analyses revealed no imbalances in Patient 1 whereas loss of Xp (~52 Mb) and duplication of Xq (~44 Mb) and 21q were confirmed in Patient 2. Conclusion: Our observations further document the cytogenetic heterogeneity and predominant paternal origin of certain de novo X-chromosome rearrangements.
Forensic Science International, 1999
Six amplified fragment length polymorphisms or Amp-FLPs, two VNTRs (D1S80 and APO-B) and four STR... more Six amplified fragment length polymorphisms or Amp-FLPs, two VNTRs (D1S80 and APO-B) and four STRs (VWA, TH01, CSF1PO and HPRTB), were typed in a Mexican population of the Jalisco state by means of non-denaturing polyacrylamide gel electrophoresis (native PAGE) in standard gel units and silver staining. Genotype distribution was in agreement with Hardy-Weinberg expectations (HWE) for all six markers. Heterozygosity ranged from 70.6 to 83.5%, the cumulated chance of exclusion (CE) and power of discrimination (PD) were 99.4 and 99.99%, respectively. STRs and D1S80 allele frequency distributions (AFD) were similar (P > 0.05) to U.S. Hispanics, but different to U.S. Caucasians and African-Americans. APO-B exhibited similarities with White Brazilians, Spaniards, but differences (P < 0.05) with Amerindian and Black Brazilians.
American Journal of Hematology, 2007
Hemophilia A (HA) is one of the most common inherited bleeding disorders caused by FVIII gene mut... more Hemophilia A (HA) is one of the most common inherited bleeding disorders caused by FVIII gene mutations. Inversion of intron 22 (inv22) originates 50% of cases of severe HA and is a major risk factor for inhibitor development. Inversion of intron 1 (inv1) has been reported to occur in 2-3% of severe HA patients. We studied both inversions to determine their frequencies in Mexican patients with severe HA and to compare these data with other HA populations. The inv22 was evaluated as a risk factor for FVIII inhibitor development in severe HA patients. We studied 44 patients from 31 severe HA families for the detection of inv22 and 94 patients from 65 families to detect inv1. We used the subcycling long-distance PCR to detect inv22 and rapid PCR in duplex reactions to detect inv1. We found a frequency of 45% for the inv22 and no inv1-positive patients (0%). These frequencies were not statistically different from other populations, although haplotype analyses of FVIII gene and telomeric regions should be incorporated to explore population-specific variation of inv1 frequencies. Inv22-positive patients showed 1.88X higher risk for developing inhibitors with respect to patients carrying other severe mutations; however, this OR value was not significant. Our findings confirm inv22 as a hot-spot for severe HA and evidence the low frequency of inv1 in a Mexican population. The non-significant risk for developing inhibitors among inv22-positive patients agrees with the variety of genetic and non-genetic factors involved in such a complication. Am.
The Tohoku Journal of Experimental Medicine
Since the middle of the last century, there have been amazing therapeutic advances for hemophilia... more Since the middle of the last century, there have been amazing therapeutic advances for hemophilia such as the development of plasma-derived products and bioengineered recombinant factors VIII and IX (for hemophilia A and B, respectively) with improved stability, higher activity, and extended half-life. The recent use of a monoclonal antibody that mimics factor VIII activity (which is an efficient treatment for all hemophilia A phenotypes with or without inhibitors) has shown the great possibilities of non-factor therapies for improving the quality of life of hemophilia A patients, with a safer application and long-lasting effects. Gene therapy offers the promise of a "true cure" for hemophilia based on the permanent effect that a gene edition may render. Clinical trials developed in the last decade based on adenoviral vectors show modest but consistent results; now, CRISPR/Cas technology (which is considered the most efficient tool for gene edition) is being developed on different hemophilia models. Once the off-target risks are solved and an efficient switch on/off for Cas activity is developed, this strategy might become the most feasible option for gene therapy in hemophilia and other monogenic diseases.
Human Mutation, 2000
The factor IX gene (F9) is a valuable model for studying germ-line mutations. Nine mutations were... more The factor IX gene (F9) is a valuable model for studying germ-line mutations. Nine mutations were detected in nine Mexican patients with hemophilia B by direct sequencing using genomic amplification with transcript sequencing (GAWTS): six single base changes, one micro-deletion, and two large deletions. Germline origins of mutations were found in three of six families with sporadic cases. Curiously, the four independent single base substitutions which were not at CpG dinucleotides occurred at only two different nucleotide positions (17,678 and 17,747) one transition and one transversion at each. The two remaining substitutions were identical changes at a CpG dinucleotide, but were determined to be independent by germline origin analysis. A statistical analysis suggests that the independent recurrence of mutations at these locations may reflect an unusual aspect of F9 mutagenesis in the Mexican population. These data raise the possibility of population-specific differences in human germline mutations.
Gaceta Medica De Mexico, 2015
The diagnosis of von Willebrand disease (vWD) is complex and requires several screening and confi... more The diagnosis of von Willebrand disease (vWD) is complex and requires several screening and confirmation tests, such as the analysis of vWF multimers, which is considered the gold standard for vWD subtyping; however, it only discriminates 2A subtype while the 2B, 2M, and 2N subtypes require additional tests and even genetic testing for final confirmation. It is important to consider the patients’ hemotype for the vWD diagnosis, particularly in Mexico where hemotype “O” predominates and may entail a 20-25% decreased level of plasma vWF and increased bleeding tendency. (Gac Med Mex. 2015;151:399-402) Corresponding author: Ana Rebeca Jaloma Cruz, arjaloma@gmail.com
![Research paper thumbnail of [The skin as a vehicle for gene therapy: hemophilia B, an application model]](https://attachments.academia-assets.com/76537668/thumbnails/1.jpg)
](Gaceta medica de Mexico, 2015
Artificial skin offers important advantages in gene therapy tor its biosafety and simple monitori... more Artificial skin offers important advantages in gene therapy tor its biosafety and simple monitoring. An easy access of keratinocytes through small biopsies and their in vitro expansion enriched with epithelial stem cells, make them an ideal target for long-term therapeutic transgene expression. Corrective cutaneous gene therapy has been recently applied in clinical trials on dermatological genetic diseases. In systemic monogenic diseases such as hemophilia B, the graft of genetically modified skin in murine experimental models has achieved a modest increase of clotting factor IX in plasma that may attenuate severe symptoms of the disease.
Haemophilia, 2020
Von Willebrand disease (VWD) is the most common inherited bleeding disorder with a prevalence of ... more Von Willebrand disease (VWD) is the most common inherited bleeding disorder with a prevalence of 0.1%, characterised by quantitative or functional deficiency of von Willebrand factor (VWF). VWD diagnosis is based on symptomology, biochemical and genetic tests, but limited laboratory resources and VWD heterogeneity still generate an important subdiagnosis gap worldwide and in our country.
Gaceta medica de Mexico, 2008
X chromosome inactivation is a stochastic event that occurs early in female embryo development to... more X chromosome inactivation is a stochastic event that occurs early in female embryo development to achieve dosage compensation with males. Certain genetic mechanisms affect the normal process causing a skewed X inactivation pattern which has clinical relevance in female carriers of X-linked recessive disorders, like haemophilia. The most commonly used assay to evaluate the X inactivation pattern is the PCR amplification of the human androgen receptor gene (HUMARA). The use of this technique in bleeding carriers and women with haemophilia allows identifying if their hemorrhagic symptoms are due to an unfavourable lyonization. Furthermore, these studies are important for understanding the X chromosome inactivation process in humans.
Iatreia, 2010
INTRODUCCION: el fenotipo clinico de hemofilia B (HB) frecuentemente varia entre los individuos c... more INTRODUCCION: el fenotipo clinico de hemofilia B (HB) frecuentemente varia entre los individuos con la misma mutacion e igual nivel del factor IX. Sin embargo se asume que otros factores independientes a la deficiencia del FIX tienen influencia en la presentacion clinica y tendencia al sangrado. Estas mutaciones adicionales (FVLeiden, FII20210 y MTHFR C677T) causantes del riesgo trombotico pueden explicar esta variacion en el fenotipo clinico al incrementar la produccion de trombina, la cual puede ser determinada por medio del ensayo de la generacion de trombina (Hemker 1993), el cual provee mas informacion que un ensayo de coagulacion. MATERIAL Y METODOS: tres pacientes provenientes de una familia con hemofilia B (HB) fueron estudiados, dos hermanos (HB1 y HB2) y un primo (HB3) todos con niveles de FIX:C 4) y HB2 (1.48). La produccion de trombina aumento cuando se agrego FIX exogeno (0.5 y 1.0u/μl) solo en un paciente (HB3) CONCLUSION: el ensayo de la generacion de trombina y los f...
![Research paper thumbnail of [Diagnostic algorithm for von Willebrand Disease (vWD) in a Mexican population]](https://attachments.academia-assets.com/76537665/thumbnails/1.jpg)
](Gaceta medica de Mexico, 2015
The diagnosis of von Willebrand disease (vWD) is complex and requires several screening and confi... more The diagnosis of von Willebrand disease (vWD) is complex and requires several screening and confirmation tests, such as the analysis of vWF multimers, which is considered the gold standard for vWD subtyping; however, it only discriminates 2A subtype while the 2B, 2M, and 2N subtypes require additional tests and even genetic testing for final confirmation. It is important to consider the patients’ hemotype for the vWD diagnosis, particularly in Mexico where hemotype “O” predominates and may entail a 20-25% decreased level of plasma vWF and increased bleeding tendency.
Various inherited bleeding disorders deserve careful medical management due to their implications... more Various inherited bleeding disorders deserve careful medical management due to their implications in women's health. In both hemophilia A and B, almost exclusively, males are affected while carrier females are generally asymptomatic. Nevertheless, carriers may present important bleeding tendencies, which can eventually constitute a serious threat to life, especially after surgery or postpartum. In addition, in rare but significant cases, some genetic mechanisms have been found to cause hemophilia in females. Aside from von Willebrand disease, which is the most widespread and better described hemorrhagic condition in women, platelet disorders and some rare clotting deficiencies cause a wide variety of mucocutaneous bleedings, menorrhagia, or postpartum bleeding, hence constituting an important health risk. A review of the genetic and pathophysiological aspects as well as main clinical complications of all these conditions will allow for preventive practices aimed at improving the quality of life of women with bleeding disorders.
Blood Cells Molecules and Diseases, Jul 1, 2020
INTRODUCTION Molecular analysis in haemophilia is currently used in the diagnosis, treatment and ... more INTRODUCTION Molecular analysis in haemophilia is currently used in the diagnosis, treatment and prognosis of this disease. Hispanic populations in Latin America have been of interest to researchers due to the reportedly high prevalence of inhibitors in these patients. AIM To perform next-generation sequencing (NGS) in a cohort of Mexican patients with HA and HB and correlate with clinical phenotypes. METHODS Patients with Haemophilia A (HA) or haemophilia B (HB), were evaluated using NGS with an Ion AmpliSeq Custom Panel. Odds ratios (ORs) for associations between F8 variants and inhibitors were obtained. RESULTS A total of 85 patients (60 with HA and 25 with HB) were included. Pathogenic variants in F8 were found in 93.3% of HA patients and in F9 in 96% of HB patients. Twelve novel potentially pathogenic variants were found. Inhibitors were observed in 20% of patients with severe HA. Four patients clinically diagnosed with HA were negative for F8 variants. CONCLUSION Overall detection rate of pathogenic variants in F8 and F9 genes was 94.6%. We identified 12 non previously reported variants and pathogenic variants in other coagulation related genes. Molecular diagnosis of HA and HB permits better options for management, assessment and genetic counseling.
Taiwanese Journal of Obstetrics and Gynecology, 2016
Objective: We report on two rare Xq rearrangements, namely a t(X;9)(q24;q12) found in a mildly-af... more Objective: We report on two rare Xq rearrangements, namely a t(X;9)(q24;q12) found in a mildly-affected girl (Patient 1) and a rea(X)dup q concomitant with a rob(14;21)mat in a Down syndrome girl (Patient 2). Case report: Both rearrangements were characterized by banding techniques [Giemsa (G), constitutive heterochromatin (C), and bromodeoxyuridine (BrdU) pulse], fluorescence in situ hybridization (FISH) assays, human androgen receptor (HUMAR) assays, and microarray analyses. Patient 1 had a t(X;9)(q24;q12)dn. Patient 2 had a de novo rea(X)(qter/q23 or q24::p11.2/qter) concomitant with an unbalanced rob(14;21)mat. X-Inactivation studies in metaphases and DNA revealed a fully skewed inactivation: the normal homolog was silenced in Patient 1 and the rea(X) in Patient 2. Both rearranged X chromosomes were of paternal descent. Microarray analyses revealed no imbalances in Patient 1 whereas loss of Xp (~52 Mb) and duplication of Xq (~44 Mb) and 21q were confirmed in Patient 2. Conclusion: Our observations further document the cytogenetic heterogeneity and predominant paternal origin of certain de novo X-chromosome rearrangements.
Forensic Science International, 1999
Six amplified fragment length polymorphisms or Amp-FLPs, two VNTRs (D1S80 and APO-B) and four STR... more Six amplified fragment length polymorphisms or Amp-FLPs, two VNTRs (D1S80 and APO-B) and four STRs (VWA, TH01, CSF1PO and HPRTB), were typed in a Mexican population of the Jalisco state by means of non-denaturing polyacrylamide gel electrophoresis (native PAGE) in standard gel units and silver staining. Genotype distribution was in agreement with Hardy-Weinberg expectations (HWE) for all six markers. Heterozygosity ranged from 70.6 to 83.5%, the cumulated chance of exclusion (CE) and power of discrimination (PD) were 99.4 and 99.99%, respectively. STRs and D1S80 allele frequency distributions (AFD) were similar (P > 0.05) to U.S. Hispanics, but different to U.S. Caucasians and African-Americans. APO-B exhibited similarities with White Brazilians, Spaniards, but differences (P < 0.05) with Amerindian and Black Brazilians.
American Journal of Hematology, 2007
Hemophilia A (HA) is one of the most common inherited bleeding disorders caused by FVIII gene mut... more Hemophilia A (HA) is one of the most common inherited bleeding disorders caused by FVIII gene mutations. Inversion of intron 22 (inv22) originates 50% of cases of severe HA and is a major risk factor for inhibitor development. Inversion of intron 1 (inv1) has been reported to occur in 2-3% of severe HA patients. We studied both inversions to determine their frequencies in Mexican patients with severe HA and to compare these data with other HA populations. The inv22 was evaluated as a risk factor for FVIII inhibitor development in severe HA patients. We studied 44 patients from 31 severe HA families for the detection of inv22 and 94 patients from 65 families to detect inv1. We used the subcycling long-distance PCR to detect inv22 and rapid PCR in duplex reactions to detect inv1. We found a frequency of 45% for the inv22 and no inv1-positive patients (0%). These frequencies were not statistically different from other populations, although haplotype analyses of FVIII gene and telomeric regions should be incorporated to explore population-specific variation of inv1 frequencies. Inv22-positive patients showed 1.88X higher risk for developing inhibitors with respect to patients carrying other severe mutations; however, this OR value was not significant. Our findings confirm inv22 as a hot-spot for severe HA and evidence the low frequency of inv1 in a Mexican population. The non-significant risk for developing inhibitors among inv22-positive patients agrees with the variety of genetic and non-genetic factors involved in such a complication. Am.
The Tohoku Journal of Experimental Medicine
Since the middle of the last century, there have been amazing therapeutic advances for hemophilia... more Since the middle of the last century, there have been amazing therapeutic advances for hemophilia such as the development of plasma-derived products and bioengineered recombinant factors VIII and IX (for hemophilia A and B, respectively) with improved stability, higher activity, and extended half-life. The recent use of a monoclonal antibody that mimics factor VIII activity (which is an efficient treatment for all hemophilia A phenotypes with or without inhibitors) has shown the great possibilities of non-factor therapies for improving the quality of life of hemophilia A patients, with a safer application and long-lasting effects. Gene therapy offers the promise of a "true cure" for hemophilia based on the permanent effect that a gene edition may render. Clinical trials developed in the last decade based on adenoviral vectors show modest but consistent results; now, CRISPR/Cas technology (which is considered the most efficient tool for gene edition) is being developed on different hemophilia models. Once the off-target risks are solved and an efficient switch on/off for Cas activity is developed, this strategy might become the most feasible option for gene therapy in hemophilia and other monogenic diseases.
Human Mutation, 2000
The factor IX gene (F9) is a valuable model for studying germ-line mutations. Nine mutations were... more The factor IX gene (F9) is a valuable model for studying germ-line mutations. Nine mutations were detected in nine Mexican patients with hemophilia B by direct sequencing using genomic amplification with transcript sequencing (GAWTS): six single base changes, one micro-deletion, and two large deletions. Germline origins of mutations were found in three of six families with sporadic cases. Curiously, the four independent single base substitutions which were not at CpG dinucleotides occurred at only two different nucleotide positions (17,678 and 17,747) one transition and one transversion at each. The two remaining substitutions were identical changes at a CpG dinucleotide, but were determined to be independent by germline origin analysis. A statistical analysis suggests that the independent recurrence of mutations at these locations may reflect an unusual aspect of F9 mutagenesis in the Mexican population. These data raise the possibility of population-specific differences in human germline mutations.
Gaceta Medica De Mexico, 2015
The diagnosis of von Willebrand disease (vWD) is complex and requires several screening and confi... more The diagnosis of von Willebrand disease (vWD) is complex and requires several screening and confirmation tests, such as the analysis of vWF multimers, which is considered the gold standard for vWD subtyping; however, it only discriminates 2A subtype while the 2B, 2M, and 2N subtypes require additional tests and even genetic testing for final confirmation. It is important to consider the patients’ hemotype for the vWD diagnosis, particularly in Mexico where hemotype “O” predominates and may entail a 20-25% decreased level of plasma vWF and increased bleeding tendency. (Gac Med Mex. 2015;151:399-402) Corresponding author: Ana Rebeca Jaloma Cruz, arjaloma@gmail.com
Gaceta medica de Mexico, 2015
Artificial skin offers important advantages in gene therapy tor its biosafety and simple monitori... more Artificial skin offers important advantages in gene therapy tor its biosafety and simple monitoring. An easy access of keratinocytes through small biopsies and their in vitro expansion enriched with epithelial stem cells, make them an ideal target for long-term therapeutic transgene expression. Corrective cutaneous gene therapy has been recently applied in clinical trials on dermatological genetic diseases. In systemic monogenic diseases such as hemophilia B, the graft of genetically modified skin in murine experimental models has achieved a modest increase of clotting factor IX in plasma that may attenuate severe symptoms of the disease.
Haemophilia, 2020
Von Willebrand disease (VWD) is the most common inherited bleeding disorder with a prevalence of ... more Von Willebrand disease (VWD) is the most common inherited bleeding disorder with a prevalence of 0.1%, characterised by quantitative or functional deficiency of von Willebrand factor (VWF). VWD diagnosis is based on symptomology, biochemical and genetic tests, but limited laboratory resources and VWD heterogeneity still generate an important subdiagnosis gap worldwide and in our country.
Gaceta medica de Mexico, 2008
X chromosome inactivation is a stochastic event that occurs early in female embryo development to... more X chromosome inactivation is a stochastic event that occurs early in female embryo development to achieve dosage compensation with males. Certain genetic mechanisms affect the normal process causing a skewed X inactivation pattern which has clinical relevance in female carriers of X-linked recessive disorders, like haemophilia. The most commonly used assay to evaluate the X inactivation pattern is the PCR amplification of the human androgen receptor gene (HUMARA). The use of this technique in bleeding carriers and women with haemophilia allows identifying if their hemorrhagic symptoms are due to an unfavourable lyonization. Furthermore, these studies are important for understanding the X chromosome inactivation process in humans.
Iatreia, 2010
INTRODUCCION: el fenotipo clinico de hemofilia B (HB) frecuentemente varia entre los individuos c... more INTRODUCCION: el fenotipo clinico de hemofilia B (HB) frecuentemente varia entre los individuos con la misma mutacion e igual nivel del factor IX. Sin embargo se asume que otros factores independientes a la deficiencia del FIX tienen influencia en la presentacion clinica y tendencia al sangrado. Estas mutaciones adicionales (FVLeiden, FII20210 y MTHFR C677T) causantes del riesgo trombotico pueden explicar esta variacion en el fenotipo clinico al incrementar la produccion de trombina, la cual puede ser determinada por medio del ensayo de la generacion de trombina (Hemker 1993), el cual provee mas informacion que un ensayo de coagulacion. MATERIAL Y METODOS: tres pacientes provenientes de una familia con hemofilia B (HB) fueron estudiados, dos hermanos (HB1 y HB2) y un primo (HB3) todos con niveles de FIX:C 4) y HB2 (1.48). La produccion de trombina aumento cuando se agrego FIX exogeno (0.5 y 1.0u/μl) solo en un paciente (HB3) CONCLUSION: el ensayo de la generacion de trombina y los f...
Gaceta medica de Mexico, 2015
The diagnosis of von Willebrand disease (vWD) is complex and requires several screening and confi... more The diagnosis of von Willebrand disease (vWD) is complex and requires several screening and confirmation tests, such as the analysis of vWF multimers, which is considered the gold standard for vWD subtyping; however, it only discriminates 2A subtype while the 2B, 2M, and 2N subtypes require additional tests and even genetic testing for final confirmation. It is important to consider the patients’ hemotype for the vWD diagnosis, particularly in Mexico where hemotype “O” predominates and may entail a 20-25% decreased level of plasma vWF and increased bleeding tendency.