Ariadna González-del Angel

Association of Interactions Among the IRF6 Gene, the 8q24 Region, and Maternal Folic Acid Intake With Non-Syndromic Cleft Lip/Palate in Mexican Mestizos

Association of Interactions Among the IRF6 Gene, the 8q24 Region, and Maternal Folic Acid Intake With Non-Syndromic Cleft Lip/Palate in Mexican Mestizos Jos!e A. Vel!azquez-Arag!on, Miguel A. Alc!antara-Ortigoza, Bernardette Estandia-Ortega, Miriam E. Reyna-Fabi!an, Carlos Cruz-Fuentes, Sandra Villag!omez, and Ariadna Gonz!alez-del Angel* Laboratorio de Biolog!ia Molecular, Departamento de Gen!etica Humana, Instituto Nacional de Pediatr!ia, Avenida Insurgentes Sur 3700-C, Insurgentes Cuicuilco, Coyoac!an, Distrito Federal, Mexico Departamento de Gen!etica, Subdirecci!on de Investigaciones Cl!inicas, Instituto Nacional de Psiquiatr!ia Ram!on de la Fuente, Calzada M!exico-Xochimilco 101, San Lorenzo Huipulco, Tlalpan, Distrito Federal, Mexico Unidad de Apoyo a la Investigaci!on Cl!inica, Subdirecci!on de Investigaci!on M!edica, Instituto Nacional de Pediatr!ia, Avenida Insurgentes Sur 3700-C, Insurgentes Cuicuilco, Coyoac!an, Distrito Federal, Mexico

Chromosome instability with bleomycin and x‐ray hypersensitivity in a boy with Nijmegen breakage syndrome

We report on a Mexican boy with microcephaly, short stature, and a high frequency of chromosome aberrations with rearrangements involving chromosomes 7 and 14, typical of ataxia telangiectasia (AT) patients. He had neither ataxia nor telangiectasia, and his immunological status and serum alpha feto protein (AFP) level were normal. Bleomycin hypersensitivity, which has been demon-strated in AT patients, was tested in the patient using AT and normal subjects for comparison. The frequency of spontaneously occurring chromosome aberrations in lymphocyte cultures was significantly higher in the patient and the AT patient than in the normal subject. Four cells from the patient showed structural rearrangements involving chromosomes 7 or 14, with breakpoints typical for AT. When exposed to 5.0 micrograms bleomycin, the lymphocytes from the AT patient showed the highest sensitivity to this agent; our patient had an intermediate sensitivity. In both patients several rearrangements involving chromosomes 7 and 14 were scored, while none were observed in the normal subject. A colony survival assay (CSA) [Huo et al., 1994: Cancer Res 54:2544-2547], using a lymphoblastoid cell line (LCL) derived from our patient, showed a survival fraction (SF) of 7%, which is in the same range as in AT patients. The clinical picture, together with the cytogenetic and radiosensitivity results, suggests that our patient fits the variable spectrum of Nijmegen breakage syndrome.

Molecular diagnosis of the fragile X and FRAXE syndromes in patients with mental retardation of unknown cause in Mexico

The fragile X syndrome (Fra-X) is the most common cause of inherited mental retardation with X-linked semi-dominant inheritance. The prevalence of Fra-X in the Mexican population is unknown. The aim of this population screening study was to determine if Fra-X or FRAXE mutations are the cause of a number of cases of mental retardation in a sample of Mexican children with mental retardation of unknown cause (MRUC) and to stress the importance of performing molecular analysis of the FMR-1 gene in all patients with MRUC. We report here the direct analysis of CGG and GCC repeats within the FMR-1 and FMR-2 genes, respectively, in 62 unrelated patients with MRUC. Two male index cases had the CGG expansion, although they did not express the Xq27.3 fragile site cytogenetically. Fra-X diagnosis was highly suspected on a clinical basis in one of the patients, but not in the other. Both mothers were found to be premutation carriers. The molecular studies of FMR-1 showed that the proportion of MRUC patients with Fra-X is 3.2%. This frequency was not significantly different to that reported in most populations. As reported in other series, no patients with FRAXE were found in our sample. Our findings confirm that the molecular analysis of the FMR-1 gene is necessary in MRUC patients to achieve unequivocal diagnosis of fragile X syndrome, carrier premutation detection and for accurate genetic counseling.

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

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.

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 α-glucosidase Gene

Pompe disease or glycogen-storage disease type 2 (GSD2, OMIM 232300) is an autosomal recessive disorder caused by mutations in the acid α-glucosidase gene. Late-onset GSD2 resembles some limb-girdle and Becker muscular dystrophies. The screening of GSD2 through the measurement of acid α-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 α-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.

Molecular analysis of the PAX8 gene in a sample of Mexican patients with primary congenital hypothyroidism: identification of the recurrent p.Arg31His mutation.

1 Stratakis, C.A., Jenkins, R.B., Pras, E. et al. (1996) Cytogenetic and microsatellite alterations in tumors from patients with the syndrome of myxomas, spotty skin pigmentation, and endocrine overactivity (Carney complex). The Journal of Clinical Endocrinology and Metabolism, 81, 3607–3614. 2 Stratakis, C.A., Pras, E., Lin, J.-P. et al. (1995) Carney complex, a multiple endocrine neoplasia and familial lentiginosis syndrome: clinical analysis and linkage to the D2S123 locus (chromosome 2p16). American Journal of Human Genetics, 57, 54. 3 Matyakhina, L., Pack, S., Kirschner, L.S. et al. (2003) Chromosome 2 (2p16) abnormalities in Carney complex tumours. Journal of Medical Genetics, 40, 268–277. 4 Basu, A. & Sivaprasad, U. (2007) Protein kinase Cepsilon makes the life and death decision. Cellular Signalling, 19, 1633–1642. 5 Petiti, J.P., Gutiérrez, S. & De Paul, A.L. et al. (2010) GH3B6 pituitary tumor cell proliferation is mediated by PKCalpha and PKCepsilon via ERK 1/2-dependent pathway. Cellular Physiology and Biochemistry, 26, 135–146.

Erratum to: Germline Mutations in NKX2-5, GATA4, and CRELD1 are Rare in a Mexican Sample of Down Syndrome Patients with Endocardial Cushion and Septal Heart Defects [Pediatric Cardiology, 36, (2015), 802-808, DOI:10.1007/s00246-014-1091-3]

4 Unidad de Apoyo a la Investigación Clı́nica, Instituto Nacional de Pediatrı́a, Secretarı́a de Salud, Insurgentes Sur 3700-C, Insurgentes-Cuicuilco, Coyoacán, CP 04530 Mexico, Distrito Federal, Mexico 5 Unidad de Genómica y Secuenciación Masiva, Subdirección de Investigación Básica, Instituto Nacional de Cancerologı́a, San Fernando Número 22, Sección XVI, Tlalpan, CP 14080 Mexico, Distrito Federal, Mexico

CTNS gene analysis emphasizes diagnostic value of eye examination in patients with cystinosis

Classic nephropathic cystinosis (CNC) is an autosomal recessive and infrequent inborn metabolic disease that should be suspected in all children who show failure to thrive and renal Fanconi syndrome (RFS). Slit-lamp examination reveals pathognomonic corneal deposits of cystine crystals in virtually all affected individuals after 12-16 mo of age. A diagnosis of CNC is difficult to confirm in children living in Mexico and most Latin American countries, because cystine levels can be measured only at a few locations. We report the cystinosin genotype findings in 15 Latin American patients with a high clinical suspicion of CNC mainly due to RFS (n =13), although five of them lacked proper ophthalmologic assessment, despite being more than 1-year-old. Molecular analysis confirmed diagnosis of CNC in six (40%) of the 15 patients, five of them with RFS and cystine crystals. The remaining nine (60%) patients had a normal genotype. The predominance of a normal cystinosin genotype in eight of 13 patients with RFS (61.50%) reinforces the need to perform slit-lamp examinations in all patients with RFS over 1 yr of age, prior to measuring cystine or performing molecular cystinosin study, both methods not readily available throughout Latin America.

Kapur-Toriello Syndrome : Further Delineation

We report on a Mexican patient with mental retardation, cleft lip and palate, and facial anomalies characteristic of Kapur–Toriello syndrome described in 1991 by Kapur and Toriello in two sibs. The condition was considered a previously undescribed autosomal recessive disorder and only one patient has been reported since that time. The clinical manifestations observed in our patient confirm some characteristics as part of the entity. In view of rarity, it is necessary to describe additional cases.

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

BackgroundNiemann-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 presentationWe 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.ConclusionsWe 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.