Publications by authors named "Miguel Angel Alcántara Ortigoza"

24 Publications

  • Page 1 of 1

Genetic spectrum and clinical early natural history of glucose-6-phosphate dehydrogenase deficiency in Mexican children detected through newborn screening.

Orphanet J Rare Dis 2021 Feb 26;16(1):103. Epub 2021 Feb 26.

UGN, Instituto de Investigaciones Biomédicas, UNAM-LEIMyT, Instituto Nacional de Pediatría SS, CDMX, Mexico.

Background: Glucose-6-phosphate dehydrogenase deficiency (G6PDd) newborn screening is still a matter of debate due to its highly heterogeneous birth prevalence and clinical expression, as well as, the lack of enough knowledge on its natural history. Herein, we describe the early natural clinical course and the underlying GDPD genotypes in infants with G6PDd detected by newborn screening and later studied in a single follow-up center. G6PDd newborns were categorized into three groups: group 1: hospitalized with or without neonatal jaundice (NNJ); group 2: non-hospitalized with NNJ; and group 3: asymptomatic. Frequencies of homozygous UGT1A1*28 (rs34983651) genotypes among G6PDd patients with or without NNJ were also explored.

Results: A total of 81 newborns (80 males, one female) were included. Most individuals (46.9%) had NNJ without other symptoms, followed by asymptomatic (42.0%) and hospitalized (11.1%) patients, although the hospitalization of only 3 of these patients was related to G6PDd, including NNJ or acute hemolytic anemia (AHA). Nine different G6PDd genotypes were found; the G6PD A genotype was the most frequent (60.5%), followed by the G6PD A (22.2%) and the Union-Maewo (rs398123546, 7.4%) genotypes. These genotypes produce a wide range of clinical and biochemical phenotypes with significant overlapping residual enzymatic activity values among class I, II or III variants. Some G6PD A individuals had enzymatic values that were close to the cutoff value (5.3 U/g Hb, 4.6 and 4.8 U/g Hb in the groups with and without NNJ, respectively), while others showed extremely low enzymatic values (1.1 U/g Hb and 1.4 U/g Hb in the groups with and without NNJ, respectively). Homozygosity for UGT1A1*28 among G6PDd patients with (11.9%, N = 5/42) or without (10.3%, N = 4/39) NNJ did not shown significant statistical difference (p = 0.611).

Conclusion: Wide variability in residual enzymatic activity was noted in G6PDd individuals with the same G6PD genotype. This feature, along with a documented heterogeneous mutational spectrum, makes it difficult to categorize G6PD variants according to current WHO classification and precludes the prediction of complications such as AHA, which can occur even with > 10% of residual enzymatic activity and/or be associated with the common and mild G6PD A and G6PD A haplotypes.
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http://dx.doi.org/10.1186/s13023-021-01693-9DOI Listing
February 2021

Diagnosis of Laron syndrome using monoplex-polymerase chain reaction technology with a whole-genome amplification template: A case report.

World J Clin Cases 2019 Dec;7(23):4029-4035

Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), México City 07360, México.

Background: Laron syndrome (LS) is an autosomal recessive hereditary condition affecting only 1/1000000 births. The cause is associated with mutations in the growth hormone (GH) receptor (GHR), leading to GH insensitivity. LS patients typically present with severe growth retardation, obesity, and abnormal sexual maturation. Currently, LS diagnosis is performed post-delivery. Therefore, we assessed the efficiency of Pre-implantation Genetic Testing (PGT) coupled with monoplex-polymerase chain reaction (PCR) technology for detecting this monogenic disease in embryos from a couple confirmed as LS heterozygous carriers.

Case Summary: The couple LS-carriers were confirmed by the presence of a first child born with LS. The couple underwent a standard fertilization (IVF) protocol. DNA was collected from trophectoderm cells from day 5 embryos. Whole genome amplification (WGA) was performed using a Sureplex DNA Amplification System and analyzed by PCR, targeting the deletion of the exons 5 and 6 in the gene as well as PGT by Next-generation Sequencing (Illumina). Eleven embryos were collected and analyzed. 27.3% were the wild type for GHR, 45.5% were heterozygotes, and 18.2% homozygous mutants. One embryo yielded no results. Three 2-embryos transfers were performed; 2 normal homozygous and four heterozygous carriers were selected for transfer. The first two transfers were unsuccessful, whereas the final transfer with two heterozygous embryos resulted in clinical pregnancy. The genomic composition of the fetus was verified, applying the same techniques using amniocytes, extracted after 21 wk of the ongoing pregnancy. The fetus was confirmed as GHR deletion in exon 5-6, carrier. A non-affected baby was born.

Conclusion: Here, we present a case demonstrating that using WGA as a template in addition to PCR targeting specific gene regions, exons 5 and 6 on the gene, could identify LS carrier embryos. This provides evidence that WGA and PCR serve as an excellent tool to detect this specific monogenic disease in IVF embryos, thus allowing selection of candidate embryos for transfer successfully when a specific inherited genetic mutation/disease is suspected.
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http://dx.doi.org/10.12998/wjcc.v7.i23.4029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906563PMC
December 2019

Predominance of Dystrophinopathy Genotypes in Mexican Male Patients Presenting as Muscular Dystrophy with A Normal Multiplex Polymerase Chain Reaction Gene Result: A Study Including Targeted Next-Generation Sequencing.

Genes (Basel) 2019 10 29;10(11). Epub 2019 Oct 29.

Servicio de Neurología Pediátrica, Dirección Médica, Instituto Nacional de Pediatría, Secretaría de Salud, Insurgentes Sur 3700-C, Colonia Insurgentes-Cuicuilco, Alcaldía Coyoacán, 04530 Ciudad de Mexico, Mexico.

The complete mutational spectrum of dystrophinopathies and limb-girdle muscular dystrophy (LGMD) remains unknown in Mexican population. Seventy-two unrelated Mexican male patients (73% of pediatric age) with clinical suspicion of muscular dystrophy and no evidence of gene deletion on multiplex polymerase chain reaction (mPCR) analysis were analyzed by multiplex ligation-dependent probe amplification (MLPA). Those with a normal result were subjected to Sanger sequencing or to next-generation sequencing for plus 10 selected LGMD-related genes. We achieved a diagnostic genotype in 80.5% ( = 58/72) of patients with predominance of dystrophinopathy-linked genotypes (68%, = 49/72), followed by autosomal recessive LGMD-related genotypes (types 2A-R1, 2C-R5, 2E-R4, 2D-R3 and 2I-R9; 12.5%, = 9/72). MLPA showed 4.2% of false-negatives for deletions assessed by mPCR. Among the small variants, 96.5% ( = 28/29) corresponded to null-alleles, most of which (72%) were inherited through a carrier mother. The p.[Leu276Ile]; [Asn463Asp] genotype is reported for the first time in Mexican patients as being associated with dilated cardiomyopathy. Absence of dysferlinopathies could be related to the small sample size and/or the predominantly pediatric age of patients. The employed strategy seems to be an affordable diagnosis approach for Mexican muscular dystrophy male patients and their families.
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http://dx.doi.org/10.3390/genes10110856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895915PMC
October 2019

Mutational spectrum of Mexican patients with tyrosinemia type 1: In silico modeling and predicted pathogenic effect of a novel missense FAH variant.

Mol Genet Genomic Med 2019 12 30;7(12):e937. Epub 2019 Sep 30.

Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, CDMX, México.

Background: Tyrosinemia type 1 (HT1, MIM#276700) is caused by a deficiency in fumarylacetoacetate hydrolase (FAH) and it is associated with severe liver and renal disfunction. At present, the mutational FAH (15q25.1, MIM*613871) spectrum underlying HT1 in the Mexican population is unknown. The objective of this study was to determine the FAH genotypes in eight nonrelated Mexican patients with HT1, who were diagnosed clinically.

Methods: Sequencing of FAH and their exon-intron boundaries and in silico protein modeling based on the crystallographic structure of mouse FAH.

Results: We identified pathogenic variants in 15/16 studied alleles (93.8%). Nine different variants were found. The most commonly detected HT1-causing allele was NM_000137.2(FAH):c.3G > A or p.(?) [rs766882348] (25%, n = 4/16). We also identified a novel missense variant NM_000137.2(FAH):c.36C > A or p.(Phe12Leu) in a homozygous patient with an early and fatal acute form. The latter was classified as a likely pathogenic variant and in silico protein modeling showed that Phe-12 residue substitution for Leu, produces a repulsion in all possible Leu rotamers, which in turn would lead to a destabilization of the protein structure and possible loss-of-function.

Conclusion: HT1 patients had a heterogeneous mutational and clinical spectrum and no genotype-phenotype correlation could be established.
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http://dx.doi.org/10.1002/mgg3.937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900384PMC
December 2019

Skewed X-inactivation in a Female Carrier with X-linked Chronic Granulomatous Disease.

Iran J Allergy Asthma Immunol 2019 Aug 17;18(4):447-451. Epub 2019 Aug 17.

Immunodeficiencies Research Unit, National Institute of Pediatrics, Mexico City, Mexico.

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defective phagocytic NADPH oxidase, causing a complete lack or significant decrease in the production of microbicidal reactive oxygen metabolites. It mainly affects male children; however, there are scarce reports of adult females diagnosed with X-linked-CGD attributed to an extremely skewed X-chromosome inactivation. This condition is characterized by severe and recurrent infections that usually develop after childhood. In clinical practice, physicians who usually confront these patients should suspect this entity and differentiate it from a secondary immunodeficiency. Here, we report a 38-year-old Mexican female with juvenile-onset X linked-CGD, caused by a de novo mutation and extremely skewed X-inactivation, whose clinical features were similar to those in patients with classic X-linked-CDG.
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http://dx.doi.org/10.18502/ijaai.v18i4.1425DOI Listing
August 2019

Report of a patient with a de novo non-recurrent duplication of 17p11.2p12 and Yq11 deletion.

Mol Cytogenet 2019 1;12:35. Epub 2019 Aug 1.

1Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Ciudad de México, México.

Background: The 17p11.2p12 locus is an unstable region that is predisposed to several known genomic disorders and non-recurrent rearrangements that yield varied and wide-ranging phenotypes. Nearly 1% of male newborns have deletions in the Y chromosome; these events primarily involve the heterochromatic region, but may extend to euchromatic Yq segments containing azoospermia factor regions.

Case Presentation: We describe the occurrence of two independent chromosomal rearrangements that originated as de novo events in a single male patient: a 10.8-Mb duplication of 17p11.2p12 and a 14.7-Mb deletion of Yq11. This individual shares some clinical characteristics with previously described patients having one or the other of these rearrangements, including global developmental delay, short stature, hypotonia, delayed puberty, certain facial features and a generalized demyelinating sensory-motor polyneuropathy without clinical manifestation. Our patient also presents some features that were not previously described in relevant individuals, including camptodactyly, preauricular pits and hypertrichosis of the back and elbows.

Conclusions: To our knowledge, this is the first patient to be reported with independent de novo deletion/duplication events involving chromosomes 17 and Y. We discuss possible responsible mechanisms and address the phenotype, particularly in light of the clinical features that were not previously reported for patients bearing a duplication of 17p11.2p12 or a deletion of Yq11. We suggest that some of the previously reported patients with Yq11 deletion and clinical manifestations other than male infertility may have additional chromosomal imbalances that could be identified by chromosome microarray analysis, as illustrated by the present case.
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http://dx.doi.org/10.1186/s13039-019-0438-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6670163PMC
August 2019

Gene Variants in Do Not Represent a Major Etiological Factor of Primary Congenital Hypothyroidism in Mexican Population.

J Pediatr Genet 2019 Jun 2;8(2):41-46. Epub 2019 Jan 2.

Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Ciudad de México, México.

Congenital hypothyroidism (CH), attributable to thyroid dysgenesis (TD), has an unusually high prevalence in Mexican population but the causes are unknown. , as a candidate gene, was subjected to automated Sanger sequencing in 122 unrelated Mexican patients with CH/TD. Although this study includes the largest number of TD-related CH patients in whom has been analyzed, no pathogenic variants were detected; only three benign polymorphic changes were identified. These results suggest that is not a major contributor to the etiology of CH or its high prevalence in Mexicans. Our work identifies misannotations of variants in three previous published reports.
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http://dx.doi.org/10.1055/s-0038-1676644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499623PMC
June 2019

Molecular characterization of Axenfeld-Rieger spectrum and other anterior segment dysgeneses in a sample of Mexican patients.

Ophthalmic Genet 2018 12 20;39(6):728-734. Epub 2018 Nov 20.

c Departamento de Génetica , Asociación para Evitar la Ceguera en México , México , México.

Background: Anterior segment dysgenesis (ASD) and Axenfeld-Rieger spectrum (ARS) are mainly due to PITX2 and FOXC1 defects, but it is difficult in some patients to differentiate among PITX2-, FOXC1-, PAX6- and CYP1B1-related disorders. Here, we set out to characterize the pathogenic variants (PV) in PITX2, FOXC1, CYP1B1 and PAX6 in nine unrelated Mexican ARS/ASD patients and in their available affected/unaffected relatives.

Materials And Methods: Automated Sanger sequencing of PITX2, FOXC1, PAX6 and CYP1B1 was performed; those patients without a PV were subsequently analyzed by Multiplex Ligation-dependent Probe Amplification (MLPA) for PITX2, FOXC1 and PAX6. Missense variants were evaluated with the MutPred, Provean, PMUT, SIFT, PolyPhen-2, CUPSAT and HOPE programs.

Results: We identified three novel PV in PITX2 (NM_153427.2:c.217G>A, c.233T>C and c.279del) and two in FOXC1 [NM_001453.2:c.274C>T (novel) and c.454T>A] in five ARS patients. The previously reported FOXC1 c.367C>T or p.(Gln123*) variant was identified in a patient with ASD. The ocular phenotype related to FOXC1 included aniridia, corneal opacity and early onset glaucoma, while an asymmetric ocular phenotype and aniridia were associated with PITX2. No gene rearrangements were documented by MLPA analysis, nor were any PV identified in PAX6 or CYP1B1.

Conclusions: Heterozygous PV in the PITX2 and FOXC1 genes accounted for 66% (6/9) of the ARS/ASD cases. The absence of PAX6 or CYP1B1 abnormalities could reflect our small sample size, although their analysis could be justified in ARS/ASD patients that present with congenital glaucoma or aniridia.
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http://dx.doi.org/10.1080/13816810.2018.1547911DOI Listing
December 2018

Mutational spectrum of PTS gene and in silico pathological assessment of a novel variant in Mexico.

Brain Dev 2018 Aug 21;40(7):530-536. Epub 2018 Apr 21.

Laboratory of Inborn Errors of Metabolism and Screening, National Institute of Pediatrics, Mexico City, Mexico. Electronic address:

Background: Tetrahydrobiopterin (BH4) is the cofactor for 6-pyruvoyl-tetrahydropterin synthase (PTPS); it is involved in BH4 biosynthesis and is encoded by PTS gene. Its deficiency (PTPSD) is characterized by hyperphenylalaninemia (HPA) and deficit in central monoamine neurotransmitters. We describe the clinical and mutational spectrum of five patients with PTPSD, from four unrelated Mexican families. All patients had symptomatic diagnosis and presented severe early neurological manifestations and HPA.

Methods: Clinical and biochemical data from studied patients were recorded. Responsible PTPSD genotypes was determined by direct and bidirectional Sanger DNA sequencing of the six PTS coding exons and their exon-intron borders, and these were directly searched in the available relatives. The novel PTS missense variant [NM_3000317.2:331G > T, p.(Ala111Ser)] was subjected to in silico, to predict a possible deleterious effect.

Results: Diminished fetal movements were perceived as a uniform characteristic in the studied group. DNA sequencing showed two known p.(Arg25∗) and p.(Val132TyrFs∗19) and the novel missense p.(Ala111Ser) PTS variants, the latter representing potentially a frequent PTPSD-responsible allele (50%, 4/8) in Mexican patients. In silico protein modeling analysis of the p.(Ala111Ser) variant revealed loss of hydrophobic interactions between the alanine and neighboring valines, suggesting that these changes in polarity may be detrimental for enzyme function, structure and/or stability.

Conclusions: This work contributes to the knowledge of PTPS molecular spectrum. The delayed diagnosis of these patients emphasizes the importance of considering BH4 metabolism defects in the differential diagnosis of HPA, especially for countries that are beginning their HPA newborn screening programs.
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http://dx.doi.org/10.1016/j.braindev.2018.03.014DOI Listing
August 2018

Unique association of hypochondroplasia with craniosynostosis and cleft palate in a Mexican family.

Am J Med Genet A 2018 01 17;176(1):161-166. Epub 2017 Nov 17.

Hospital Bité-Médica Santa Fe, Ciudad de México, México.

Hypochondroplasia (HCH) is a skeletal dysplasia caused by an abnormal function of the fibroblast growth factor receptor 3. Although believed to be relatively common, its prevalence and phenotype are not well established owing to its clinical, radiological, and genetic heterogeneity. Here we report on a molecularly proven HCH family with an affected father and two children. The siblings (male and female) with HCH also had craniosynostosis and cleft palate, respectively. The present report supports the conclusion that the full clinical spectrum of HCH is not completely delineated. It also suggests that secondary, as yet unknown, modifying factors can influence the final phenotype.
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http://dx.doi.org/10.1002/ajmg.a.38526DOI Listing
January 2018

Molecular Analysis Confirms that FKRP-Related Disorders are Underdiagnosed in Mexican Patients with Neuromuscular Diseases.

Neuropediatrics 2017 12 24;48(6):442-450. Epub 2017 Oct 24.

Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Ciudad de México, México.

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http://dx.doi.org/10.1055/s-0037-1607054DOI Listing
December 2017

Newborn cystic fibrosis screening in southeastern Mexico: Birth prevalence and novel CFTR gene variants.

J Med Screen 2018 09 9;25(3):119-125. Epub 2017 Oct 9.

1 Sociedad Mexicana de Errores Innatos y Tamiz, A.C., México.

Objective: To use the results of the first five years of a cystic fibrosis newborn screening program to estimate the cystic fibrosis birth prevalence and spectrum of cystic fibrosis transmembrane conductance regulator ( CFTR) gene variants in Yucatan, Mexico.

Methods: Screening was performed from 2010 to 2015, using two-tier immunoreactive trypsinogen testing, followed by a sweat test. When sweat test values were >30 mmol/L, the CFTR gene was analyzed.

Results: Of 96,071 newborns screened, a second sample was requested in 119 cases. A sweat test was performed in 30 newborns, and 9 possible cases were detected (seven confirmed cystic fibrosis and two inconclusive). The most frequently detected CFTR pathogenic variant (5/14 cystic fibrosis alleles, 35.7%) was p.(Phe508del); novel p.(Ala559Pro) and p.(Thr1299Hisfs*29) pathogenic variants were found.

Conclusions: Cystic fibrosis birth prevalence in southeastern Mexico is 1:13,724 newborns. Immunoreactive trypsinogen blood concentration is influenced by gestational age and by the time of sampling. The spectrum of CFTR gene variants in Yucatan is heterogeneous.
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http://dx.doi.org/10.1177/0969141317722808DOI Listing
September 2018

Expansion of the variable expression of Muenke syndrome: Hydrocephalus without craniosynostosis.

Am J Med Genet A 2016 12 29;170(12):3189-3196. Epub 2016 Aug 29.

Hospital de Especialidades del Niño y la Mujer "Felipe Núñez Lara", Querétaro, Mexico.

Muenke syndrome (MS) is an autosomal dominant coronal craniosynostosis syndrome with variable extracranial anomalies. We studied 56 unrelated patients with non-syndromic uni- or bicoronal craniosynostosi to identify the frequency and clinical characteristics of MS in a cohort of Mexican childrens. The FGFR3 pathogenic variation p.Pro250Arg responsible for MS was characterized in all probands by PCR-restriction assay; available first-degree relatives (15 parents, 5 siblings) of the confirmed p.Pro250Arg carriers were also tested. All heterozygotes for p.Pro250Arg underwent clinical and audiologic assessment, as well as X-ray evaluations of hands and feet. Eight of 56 probands (14%) were found to carry the p.Pro250Arg variant and half of them were familial cases. Four p.Pro250Arg heterozygous familial members had been considered unaffected before the molecular testing. In one MS family, hydrocephalus without craniosynostosis, was documented as the only clinical manifestation in a previously undetected heterozygous male sibling. Hydrocephalus without craniosynostosis in a patient with the p.Pro250Arg variant suggests that some patients with MS might present only this manifestation; to our knowledge, hydrocephalus has not been described as isolated feature in MS, so we propose to consider this feature as an expansion of the MS phenotype rather than an unrelated finding. Our data also reinforce the notion that molecular testing of FGFR3 must be included in the diagnostic approach of coronal craniosynostosis. This will allow accurate genetic counseling and optimal management of MS, which might otherwise go undiagnosed because of mild manifestations and wide variability of expression. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37951DOI Listing
December 2016

An uncommon inheritance pattern in Niemann-Pick disease type C: identification of probable paternal germline mosaicism in a Mexican family.

BMC Neurol 2016 Aug 22;16(1):147. Epub 2016 Aug 22.

Servicio de Medicina Interna, Sociedad de Beneficencia Española, Ciudad de México, México.

Background: Niemann-Pick disease type C (NP-C) is a fatal lysosomal neurodegenerative and neurovisceral disease. It is caused by defects in intracellular lipid trafficking, which lead to the accumulation of lipids and glycosphingolipids within the endosomes and lysosomes of affected individuals. Pathogenic variants of the NPC1 or NPC2 genes yield highly variable phenotypes with a time course that ranges from fetal onset (i.e., hydrops fetalis) to progressive dementia in adults. NP-C is typically inherited in an autosomal-recessive manner. To our knowledge, no previous report has identified germline mosaicism as an inheritance mechanism in NP-C.

Case Presentation: We report the case of a male Mexican patient with "variant" filipin staining and a juvenile form of NP-C attributed to compound heterozygosity for two previously reported pathogenic variants of NPC1: c.[1042C>T];[2780C>T] or p.[Arg348*];[Ala927Val]. The proband's mother and healthy sister were heterozygous carriers of the c.2780C > T (exon 18) and c.1042C > T (exon 8) variants, respectively. However, direct sequencing of exons 8 and 18 of NPC1 revealed no mutation in genomic DNA obtained from the father's peripheral blood. DNA profiling ruled out the possibility of non-paternity. We were unable to obtain a sperm sample to demonstrate paternal gonadal mosaicism. NPC1 haplotype analysis using 20 linked single nucleotide variants failed to yield sufficient information to document a p.(Arg348*) NPC1 pathogenic variant-associated haplotype in the family.

Conclusions: We propose that this case of NP-C involves paternal germline mosaicism. To the best of our knowledge, this has not previously been reported in NP-C.
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http://dx.doi.org/10.1186/s12883-016-0649-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4994172PMC
August 2016

Case report of renal tubular acidosis and misdiagnosed.

Nefrologia 2016 May-Jun;36(3):323-5. Epub 2016 Feb 5.

Laboratorio de Investigación en Nefrología y Metabolismo Mineral Óseo, Hospital Infantil de México Federico Gómez, México, D.F., México.

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http://dx.doi.org/10.1016/j.nefro.2015.10.012DOI Listing
December 2017

Effects of Fructans from Mexican Agave in Newborns Fed with Infant Formula: A Randomized Controlled Trial.

Nutrients 2015 Oct 29;7(11):8939-51. Epub 2015 Oct 29.

Unidad de Investigación Traslacional & Centro de Análisis de la Evidencia, Hospital General Dr. Manuel Gea González, Mexico City 14080, México.

Background: The importance of prebiotics consumption is increasing all over the world due to their beneficial effects on health. Production of better prebiotics from endemic plants raises possibilities to enhance nutritional effects in vulnerable population groups. Fructans derived from Agave Plant have demonstrated their safety and efficacy as prebiotics in animal models. Recently, the safety in humans of two fructans obtained from Agave tequilana (Metlin(®) and Metlos(®)) was demonstrated.

Methods: This study aimed to demonstrate the efficacy as prebiotics of Metlin(®) and Metlos(®) in newborns of a randomized, double blind, controlled trial with a pilot study design. Biological samples were taken at 20 ± 7 days, and three months of age from healthy babies. Outcomes of efficacy include impact on immune response, serum ferritin, C-reactive protein, bone metabolism, and gut bacteria changes.

Results: There were differences statistically significant for the groups of infants fed only with infant formula and with formula enriched with Metlin(®) and Metlos(®).

Conclusions: Our results support the efficacy of Metlin(®) and Metlos(®) as prebiotics in humans, and stand the bases to recommend their consumption.

Trial Registration: ClinicalTrials.gov, NCT 01251783.
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http://dx.doi.org/10.3390/nu7115442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663570PMC
October 2015

Deletion of exon 1 of the SLC16A2 gene: a common occurrence in patients with Allan-Herndon-Dudley syndrome.

Thyroid 2015 Mar 6;25(3):361-7. Epub 2015 Feb 6.

1 Laboratorio de Biología Molecular, Departamento de Genética, Instituto Nacional de Pediatría , Mexico City, Mexico.

Background: Allan-Herndon-Dudley syndrome (AHDS) is an X-linked type of mental retardation resulting from hindered thyroid hormone access to neurons. Clustered nonrecurrent deletions of SLC16A2 exon 1 have been described in three patients with AHDS. We report a fourth patient with such a deletion and discuss possible mechanisms leading to these rearrangements.

Case Presentation: A three-and-a-half-year-old male with clinical and biochemical AHDS phenotype and a history of normal neonatal screening for hypothyroidism underwent SLC16A2 molecular analysis. Unexpectedly, he showed skeletal signs of hypothyroidism.

Methods And Results: The exons of the SLC16A2 (MCT8) gene and the sequences surrounding exon 1 were amplified using PCR. The patient had a 36-kb deletion affecting exon 1 of SLC16A2. The deletion junction was subjected to bioinformatic analyses, along with two other reported exon 1 deletion junctions, identifying possible sequence features and mechanisms responsible for such genomic rearrangements.

Discussion/conclusion: This patient had a classic AHDS phenotype with an unexpectedly large anterior fontanel and delayed bone age and dentition. Bioinformatic analyses suggested that exon 1 deletions in patients with AHDS are caused by microhomology-mediated replicative-based and nonhomologous end-joining mechanisms. Rearrangement susceptibility may be due to the size of intron 1 and the percentage of repeat sequences.
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http://dx.doi.org/10.1089/thy.2014.0284DOI Listing
March 2015

Germinal mosaicism in a sample of families with Duchenne/Becker muscular dystrophy with partial deletions in the DMD gene.

Genet Test Mol Biomarkers 2014 Feb 16;18(2):93-7. Epub 2013 Nov 16.

Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría , México, D.F., México.

Germinal mosaicism should be considered when estimating the recurrence risk in families with Duchenne/Becker muscular dystrophy (D/BMD). Germinal mosaicism, however, has not been assessed in Mexican families with deletions in the DMD gene. To determine the distribution of deletions in the two hot spots and the proportion of de novo and transmitted deletions, we analyzed 153 individuals with D/BMD and a DMD partial deletion and 322 of their maternal female relatives. Predilection for the distal hot spot was observed in 112 families (73%), while gene dosage analysis of female relatives of D/BMD patients identified germinal mosaicism deletions in at least 11.6% of the patients' families, thought to result from de novo mutations. Recurrence risk due to germinal mosaicism justifies carrier detection in maternal female relatives and prenatal diagnosis in mothers of individuals with apparently de novo DMD deletions.
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http://dx.doi.org/10.1089/gtmb.2013.0384DOI Listing
February 2014

Expression of RUNX1 isoforms and its target gene BLK in childhood acute lymphoblastic leukemia.

Leuk Res 2012 Sep 29;36(9):1105-11. Epub 2012 Jun 29.

Laboratorio de Cultivo de Tejidos, Instituto Nacional de Pediatría, México, DF, Mexico.

Bone marrow samples from children with acute lymphoblastic leukemia were analyzed for the expression of RUNX1a/b/c isoforms. Obtained patterns were associated with genetic abnormalities and the expression of the RUNX1 regulated gene BLK. RUNX1c was present in all patients, but the expected over-expression of RUNX1a was not observed. Over-expression of total RUNT domain isoforms was detected in patients with extra RUNX1 copies, and unexpectedly, in those with t(4;11). Only expression of the total RUNT domain-containing isoforms and BLK presented positive correlation. Results suggest a more complex role of RUNX1 in leukemogenesis than the proposed antagonism between the isoforms.
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http://dx.doi.org/10.1016/j.leukres.2012.05.019DOI Listing
September 2012

Screening of late-onset Pompe disease in a sample of Mexican patients with myopathies of unknown etiology: identification of a novel mutation in the acid alpha-glucosidase gene.

J Child Neurol 2010 Aug 29;25(8):1034-7. Epub 2010 Mar 29.

Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, México.

Pompe disease or glycogen-storage disease type 2 (GSD2, OMIM 232300) is an autosomal recessive disorder caused by mutations in the acid alpha-glucosidase gene. Late-onset GSD2 resembles some limb-girdle and Becker muscular dystrophies. The screening of GSD2 through the measurement of acid alpha-glucosidase activity in dried blood spots was applied to a selected sample of 5 Mexican patients with proximal myopathies of unknown etiology. Only 1 male patient showed a low level of acid alpha-glucosidase activity and a compound heterozygote genotype for the c.-32-13T>G splicing mutation present in most white late-onset Pompe disease cases and the novel mutation p.C558S. To our knowledge, this is the first report of a Mexican patient with late-onset GSD2. The identification of c.-32-13T>G in our patient could reflect the genetic contribution of European ancestry to the Mexican population. The enzymatic screening of GSD2 could be justified in patients with myopathies of unknown etiology.
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http://dx.doi.org/10.1177/0883073809356035DOI Listing
August 2010

[Prenatal molecular diagnosis of a DMD carrier female fetus by chorionic villus sampling and linkage analysis].

Ginecol Obstet Mex 2009 Feb;77(2):103-9

Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatria, Mexico.

Background: Duchenne muscular dystrophy (DMD) is the most frequent inherited and lethal neuromuscular disorder in humans. Molecular prenatal diagnosis of DMD through amniocentesis is a real preventive reproductive option in our country, although experience with chorionic villus sampling is still limited (CVS).

Objective: Perform the first prenatal diagnosis in an obligate DMD carrier woman in Mexico by CVS.

Material And Method: CVS was performed in an obligate DMD carrier woman in which no partial intragenic deletions were present but a haplotype at-risk was identified. Cytogenetic analysis with GTG banding was performed and genomic DNA extraction from CVS sample was done without culture. Fetal gender assignment was achieved by ultrasonography at 12 weeks of gestation and confirmed by PCR amplification of two Y chromosome-linked loci (SRY and DYS389I/II). Identification of the DMD haplotype at-risk in the fetus was done through analysis of the intragenic markers pERT87.8/TaqI and pERT87.15/Xmnl.

Results: Absence of PCR products corresponding to Y chromosome-linked loci in DNA CVS sample was compatible with a female fetus; it was confirmed later by cytogenetic study and prenatal ultrasound follow-up. Linkage analysis reveals that the female fetus inherited the DMD haplotype at-risk. We did not identify any maternal DNA contamination in CVS molecular analysis and these results were postnatally confirmed in DNA obtained from buccal cells.

Conclusion: Molecular prenatal diagnosis through chorionic villus sampling could be an early reproductive prevention strategy applicable to Duchenne/Becker muscular dystrophy carrier women in our country.
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February 2009

Molecular analysis of the PAX6 gene in Mexican patients with congenital aniridia: report of four novel mutations.

Mol Vis 2008 Sep 8;14:1650-8. Epub 2008 Sep 8.

Department of Human Genetics, National Institute of Pediatrics, Mexico City, Mexico.

Purpose: Paired box gene 6 (PAX6) heterozygous mutations are well known to cause congenital non-syndromic aniridia. These mutations produce primarily protein truncations and have been identified in approximately 40%-80% of all aniridia cases worldwide. In Mexico, there is only one previous report describing three intragenic deletions in five cases. In this study, we further analyze PAX6 variants in a group of Mexican aniridia patients and describe associated ocular findings.

Methods: We evaluated 30 nonrelated probands from two referral hospitals. Mutations were detected by single-strand conformation polymorphism (SSCP) and direct sequencing, and novel missense mutations and intronic changes were analyzed by in silico analysis. One intronic variation (IVS2+9G>A), which in silico analysis suggested had no pathological effects, was searched in 103 unaffected controls.

Results: Almost all cases exhibited phenotypes that were at the severe end of the aniridia spectrum with associated ocular alterations such as nystagmus, macular hypoplasia, and congenital cataracts. The mutation detection rate was 30%. Eight different mutations were identified: four (c.184_188dupGAGAC, c.361T>C, c.879dupC, and c.277G>A) were novel, and four (c.969C>T, IVS6+1G>C, c.853delC, and IVS7-2A>G) have been previously reported. The substitution at position 969 was observed in two patients. None of the intragenic deletions previously reported in Mexican patients were found. Most of the mutations detected predict either truncation of the PAX6 protein or conservative amino acid changes in the paired domain. We also detected two intronic non-pathogenic variations, IVS9-12C>T and IVS2+9G>A, that had been previously reported. Because the latter variation was considered potentially pathogenic, it was analyzed in 103 healthy Mexican newborns where we found an allelic frequency of 0.1116 for the A allele.

Conclusions: This study adds four novel mutations to the worldwide PAX6 mutational spectrum, and reaffirms the finding that c.969C>T is one of the three more frequent causal mutations in aniridia cases. It also provides evidence that IVS2+9G>A is an intronic change without pathogenic effect.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2530489PMC
September 2008

Analysis of the CTNS gene in nephropathic cystinosis Mexican patients: report of four novel mutations and identification of a false positive 57-kb deletion genotype with LDM-2/exon 4 multiplex PCR assay.

Genet Test 2008 Sep;12(3):409-14

Departamento de Genética Humana, Instituto Nacional de Pediatría, México City, Distrito Federal, México.

Objective: Identify CTNS gene mutations in nephropathic cystinosis Mexican patients.

Subjects And Methods: Eleven patients were included, nine presenting infantile nephropathic cystinosis and two siblings with the juvenile phenotype. The common 57-kb deletion was detected by multiplex PCR using large deletion marker-2 (LDM-2)/exon 4 set primers. Those alleles negative for 57-kb deletion were screened by single strand confirmation polymorphism (SSCP) and subsequent direct sequencing.

Results: In our sample, five mutations previously reported are identified: 57-kb deletion, EX4_EX5del, c.985_986insA, c.357_360delGACT, and c.537_557del. We detect a false assignation of 57-kb deletion homozygous genotype by using the LDM-2/exon 4 primers. In addition, four novel and severe mutations are identified: c.379delC, c.1090_1093delACCAinsCG, c.986C>G (p.T216R), and c.400+5G>A.

Conclusions: Our sample of Mexican patients display allelic heterogeneity as compared to European or North American cystinosis cases. The identification of novel mutations might suggest the presence of exclusive American CTNS alleles in Mexican population. In order to prevent the false positive assignation of 57-kb deletion genotype, as caused by the presence of another type of intragenic CTNS gross deletion, we propose to analyze a different control CTNS exon to those originally reported in both LDM multiplex PCR assays, especially when parental DNA samples are not available.
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http://dx.doi.org/10.1089/gte.2008.0014DOI Listing
September 2008