Oocyte maturation arrest produced by TUBB8 mutations: impact of genetic disorders in infertility treatment.

Oocyte maturation defect is a challenging situation in the management of infertility, the etiology may be related to endocrine causes, protocols used in ovarian stimulation, oocyte intrinsic defects or procedures in embryology laboratory. We report three Mexican females in treatment for primary infertility with non-mature oocytes after ovary stimulation and oocyte capture in whom a genetic diagnosis of TUBB8-oocyte maturation defect was revealed by exome sequencing. Two couples achieved pregnancies though oocyte donation after establishing the genetic etiology. Our results expand the role of TUBB8-disorders in patients of non-Asian ethnicity. Oocyte maturation defects of monogenic origin are a growing group of disorders that endocrinologists and reproductive medicine specialists should be aware in order to provide referral to genetics for establish a correct and opportune diagnosis.

Natural-cycle in vitro fertilization (IVF) combined with in vitro maturation in infertile patients with polycystic ovarian syndrome (PCOS) requiring IVF.

OBJECTIVE: In this study, we report an experience of 59 natural-cycle IVF combined with in vitro oocyte maturation (IVF/M) cycles in patients with PCOS requiring IVF recruited based on limitations to afford a conventional IVF treatment in a 9-years period. Results of IVF/M were compared with 164 cycles of IVF in PCOS patients. MATERIAL AND METHODS: In IVF/M cycles only hCG priming was used before oocyte recovery, with in vitro maturation of immature oocytes in a commercial medium. In conventional IVF group, recombinant FSH (rFSH) and GnRH agonist/antagonist for ovarian stimulation were used. In both groups, fertilization was achieved by intracytoplasmic sperm injection (ICSI) of mature oocytes and fresh embryos transferred at day 2 or day 3. RESULTS: In all IVF/M cycles oocytes and transferable quality embryos were obtained, only in 6 IVF/M cycles mature oocytes were obtained at oocyte capture day. Clinical pregnancy rate per cycle was 39.0% vs 53.6% (p = 0.0682) and delivery rate per cycle was 30.5% vs 42.6% (p = 0.1209) in IVF/M and conventional IVF respectively. Patients with ovarian hyperstimulation syndrome (OHSS) were 0% in IVF/M vs 6.7% in conventional IVF (p = 0.0399). CONCLUSION: Our experience in a private clinic in Mexico suggests that IVF/M can be a useful initial strategy to treat PCOS patients requiring IVF with comparable delivery rates to conventional IVF and a decreased risk of ovary hyperstimulation. IVF/M may be indicated to patients with limited resources paying without insurance for their infertility treatment.

A recurrent de novo mutation in ATP1A3 gene in a Mexican patient with alternating hemiplegia of childhood detected by massively parallel sequencing / Mutación de novo recurrente en el gen ATP1A3 en una paciente mexicana con hemiplejia alternante de la infancia detectada por secuenciación masiva en paralelo

Abstract Background: Pediatric movement disorders represent a diagnostic challenge for pediatricians and pediatric neurologists due to their high clinical heterogeneity and shared common features. Therefore, specific diagnoses require different approaches including metabolic work-up and specific tests for frequent genetic conditions. Alternating hemiplegia of childhood (AHC) is an ultra-rare pediatric movement disorder, characterized by paroxysmal alternating hemiplegia, dystonia, and seizure-like episodes that can be misleading during the evaluation of a child with a movement disorder. Case report: We present a Mexican patient with abnormal movements referred to the Genetics clinic because of hyperammonemia and a possible organic acidemia. Our assessment did not find clinical features compatible with an inborn error of metabolism. A massively parallel sequencing approach with targeted panel sequencing was used to get a final diagnosis. A missense variant c.2839G>A (p.Gly947Arg) located at exon 21 of ATP1A3 gene was demonstrated. This variant (rs398122887) has been previously reported as de novo producing alternating hemiplegia of childhood (AHC). Conclusions: AHC is an ultra-rare syndrome presented as a movement disorder with seizure-like episodes and a unique facial phenotype. Clinicians should be aware of this combination in order to diagnose this condition in a timely manner. Massive parallel sequencing panels are emerging as the best approach to diagnose rare movement disorders and simultaneously rule out metabolic disorders and common epileptic syndromes.

Resumen Introducción: Los trastornos pediátricos del movimiento representan un reto diagnóstico para pediatras y neurólogos pediatras debido a su gran heterogeneidad clínica y características comunes compartidas. Por lo tanto, los diagnósticos específicos requieren de diferentes abordajes que incluyen la búsqueda de desórdenes metabólicos y pruebas específicas para condiciones genéticas frecuentes. La hemiplejia alternante de la infancia (AHC) es un trastorno pediátrico del movimiento poco común, caracterizado por cuadros paroxísticos de hemiplejia alternante, distonía y episodios semejantes a crisis epilépticas, que pueden resultar desorientadores durante el abordaje diagnóstico de un infante con un desorden del movimiento. Caso clínico: Presentamos una paciente mexicana con movimientos anormales referida a la Clínica de Genética por hiperamonemia y una posible acidemia orgánica. Nuestro abordaje no identificó características clínicas compatibles con un error innato del metabolismo. Se utilizó un abordaje basado en secuenciación masiva en paralelo para obtener un diagnóstico final. Se demostró una variante de sentido equivocado c.2839G>A (p.Gly947Arg) localizada en el exón 21 del gen ATP1A3. Esta variante (rs398122887) ha sido previamente reportada como de novo, ocasionando AHC. Conclusiones: La AHC es un síndrome excepcionalmente raro que se presenta con un trastorno del movimiento con cuadros semejantes a crisis epilépticas y un fenotipo facial particular. Los médicos deben ser conscientes de esta combinación con el fin de diagnosticar oportunamente esta condición. Los paneles de secuenciación masiva están emergiendo como el mejor abordaje para diagnosticar trastornos del movimiento raros y, simultáneamente, descartar trastornos metabólicos y síndromes epilépticos comunes.

A recurrent de novo mutation in ATP1A3 gene in a Mexican patient with alternating hemiplegia of childhood detected by massively parallel sequencing.

Background: Pediatric movement disorders represent a diagnostic challenge for pediatricians and pediatric neurologists due to their high clinical heterogeneity and shared common features. Therefore, specific diagnoses require different approaches including metabolic work-up and specific tests for frequent genetic conditions. Alternating hemiplegia of childhood (AHC) is an ultra-rare pediatric movement disorder, characterized by paroxysmal alternating hemiplegia, dystonia, and seizure-like episodes that can be misleading during the evaluation of a child with a movement disorder. Case report: We present a Mexican patient with abnormal movements referred to the Genetics clinic because of hyperammonemia and a possible organic acidemia. Our assessment did not find clinical features compatible with an inborn error of metabolism. A massively parallel sequencing approach with targeted panel sequencing was used to get a final diagnosis. A missense variant c.2839G>A (p.Gly947Arg) located at exon 21 of ATP1A3 gene was demonstrated. This variant (rs398122887) has been previously reported as de novo producing alternating hemiplegia of childhood (AHC). Conclusions: AHC is an ultra-rare syndrome presented as a movement disorder with seizure-like episodes and a unique facial phenotype. Clinicians should be aware of this combination in order to diagnose this condition in a timely manner. Massive parallel sequencing panels are emerging as the best approach to diagnose rare movement disorders and simultaneously rule out metabolic disorders and common epileptic syndromes.

Introducción: Los trastornos pediátricos del movimiento representan un reto diagnóstico para pediatras y neurólogos pediatras debido a su gran heterogeneidad clínica y características comunes compartidas. Por lo tanto, los diagnósticos específicos requieren de diferentes abordajes que incluyen la búsqueda de desórdenes metabólicos y pruebas específicas para condiciones genéticas frecuentes. La hemiplejia alternante de la infancia (AHC) es un trastorno pediátrico del movimiento poco común, caracterizado por cuadros paroxísticos de hemiplejia alternante, distonía y episodios semejantes a crisis epilépticas, que pueden resultar desorientadores durante el abordaje diagnóstico de un infante con un desorden del movimiento. Caso clínico: Presentamos una paciente mexicana con movimientos anormales referida a la Clínica de Genética por hiperamonemia y una posible acidemia orgánica. Nuestro abordaje no identificó características clínicas compatibles con un error innato del metabolismo. Se utilizó un abordaje basado en secuenciación masiva en paralelo para obtener un diagnóstico final. Se demostró una variante de sentido equivocado c.2839G>A (p.Gly947Arg) localizada en el exón 21 del gen ATP1A3. Esta variante (rs398122887) ha sido previamente reportada como de novo, ocasionando AHC. Conclusiones: La AHC es un síndrome excepcionalmente raro que se presenta con un trastorno del movimiento con cuadros semejantes a crisis epilépticas y un fenotipo facial particular. Los médicos deben ser conscientes de esta combinación con el fin de diagnosticar oportunamente esta condición. Los paneles de secuenciación masiva están emergiendo como el mejor abordaje para diagnosticar trastornos del movimiento raros y, simultáneamente, descartar trastornos metabólicos y síndromes epilépticos comunes.

Colestasis por deficiencia de 3β-Δ5-C27-hidroxiesteroide deshidrogenasa en un paciente con alteración en la síntesis de ácidos biliares / Cholestasis due to deficiency of 3β-Δ5-C27-hydroxysteroid dehydrogenase in a patient with altered bile acid synthesis

Resumen: Introducción: Los errores innatos en la síntesis de ácidos biliares son un grupo de defectos genéticos que representan del 1 al 2% de las enfermedades colestásicas crónicas en lactantes, niños y adolescentes. La deficiencia de 3β-Δ5-C27-hidroxiesteroide oxidoreductasa (3β-HSDH) es el defecto más comúnmente reportado. El cuadro clínico característico consiste en hepatitis neonatal, hepatomegalia, esplenomegalia, malabsorción, desnutrición y enfermedad hepática de aparición tardía. Caso clínico: Lactante masculino con antecedente de ictericia en escleras a los 4 meses que se resolvió espontáneamente; posteriormente, a los 18 meses, presentó enfermedad colestásica. Durante su abordaje se documentó gamma-glutamil transpeptidasa normal, hallazgo que es altamente sugestivo de alteración en la síntesis de ácidos biliares. El diagnóstico se realizó con espectrometría de masas en orina. Se inició tratamiento con ácido cólico oral, y presentó mejoría inmediata. Conclusiones: El resultado en los ácidos biliares urinarios es definitivo para el defecto genético y consistente con mutaciones homocigotas en el gen HSD3B7. Este padecimiento constituye un diagnóstico de exclusión en las enfermedades colestásicas de la infancia, particularmente el hallazgo de gamma-glutamil transpeptidasa normal o levemente aumentada, y responde adecuadamente al tratamiento oral, por lo que debe identificarse de forma temprana.

Abstract: Background: Inborn errors in bile acid synthesis are a group of genetic defects accounting for 1 to 2% of chronic cholestatic diseases in infants, children and adolescents. Deficiency of 3β-Δ5-C27-hydroxysteroid dehydrogenase (3β-HSDH) is the most common defect in this disease. Clinical features consist of neonatal hepatitis, hepatomegaly, splenomegaly, malabsorption, malnutrition, and late-onset liver disease. Case report: A male infant who presented jaundice in sclera at 4 months that resolved spontaneously, later presented cholestatic disease at 18 months. During his approach, normal gamma-glutamyl transpeptidase was documented, a finding that is highly suggestive of alteration in the synthesis of bile acids. The diagnosis was made using urine mass spectrometry. Oral colic acid treatment was started, presenting immediate improvement. Conclusions: The result in urinary bile acids is definitive for the genetic defect and consistent with homozygous mutations in the HSD3B7 gene. This condition is a diagnosis of exclusion in childhood cholestatic diseases, particularly in the presence of normal or mildly enlarged gamma-glutamyl transpeptidase, and responds adequately to oral treatment; it should be identified early.

[Colestasis por deficiencia de 3b-Δ5-C27-hidroxiesteroide deshidrogenasa en un paciente con alteración en la síntesis de ácidos biliares]. / Cholestasis due to deficiency of 3b-Δ5-C27-hydroxysteroid dehydrogenase in a patient with altered bile acid synthesis.

Introducción: Los errores innatos en la síntesis de ácidos biliares son un grupo de defectos genéticos que representan del 1 al 2% de las enfermedades colestásicas crónicas en lactantes, niños y adolescentes. La deficiencia de 3b-Δ5-C27-hidroxiesteroide oxidoreductasa (3b-HSDH) es el defecto más comúnmente reportado. El cuadro clínico característico consiste en hepatitis neonatal, hepatomegalia, esplenomegalia, malabsorción, desnutrición y enfermedad hepática de aparición tardía. Caso clínico: Lactante masculino con antecedente de ictericia en escleras a los 4 meses que se resolvió espontáneamente; posteriormente, a los 18 meses, presentó enfermedad colestásica. Durante su abordaje se documentó gamma-glutamil transpeptidasa normal, hallazgo que es altamente sugestivo de alteración en la síntesis de ácidos biliares. El diagnóstico se realizó con espectrometría de masas en orina. Se inició tratamiento con ácido cólico oral, y presentó mejoría inmediata. Conclusiones: El resultado en los ácidos biliares urinarios es definitivo para el defecto genético y consistente con mutaciones homocigotas en el gen HSD3B7. Este padecimiento constituye un diagnóstico de exclusión en las enfermedades colestásicas de la infancia, particularmente el hallazgo de gamma-glutamil transpeptidasa normal o levemente aumentada, y responde adecuadamente al tratamiento oral, por lo que debe identificarse de forma temprana. Background: Inborn errors in bile acid synthesis are a group of genetic defects accounting for 1 to 2% of chronic cholestatic diseases in infants, children and adolescents. Deficiency of 3b-Δ5-C27-hydroxysteroid dehydrogenase (3ß-HSDH) is the most common defect in this disease. Clinical features consist of neonatal hepatitis, hepatomegaly, splenomegaly, malabsorption, malnutrition, and late-onset liver disease. Case report: A male infant who presented jaundice in sclera at 4 months that resolved spontaneously, later presented cholestatic disease at 18 months. During his approach, normal gamma-glutamyl transpeptidase was documented, a finding that is highly suggestive of alteration in the synthesis of bile acids. The diagnosis was made using urine mass spectrometry. Oral colic acid treatment was started, presenting immediate improvement. Conclusions: The result in urinary bile acids is definitive for the genetic defect and consistent with homozygous mutations in the HSD3B7 gene. This condition is a diagnosis of exclusion in childhood cholestatic diseases, particularly in the presence of normal or mildly enlarged gamma-glutamyl transpeptidase, and responds adequately to oral treatment; it should be identified early.

[Combined Preimplantation Genetic Testing for Aneuploidy and Monogenic Disease in a Mexican Family Affected by X-linked Hypohidrotic Ectodermal Dysplasia].

Background: Hypohidrotic ectodermal dysplasia (HED) is a genetic skin condition presenting as hypohidrosis, hypodontia, and hypotrichosis, resulting in an important burden for affected families. The most common form of HED has an X-linked inheritance and female carriers have the option of prenatal or preimplantation genetic testing (PGT) to avoid transmission of the disease. A combined PGT for a mutation in EDA gene and aneuploidies in a Mexican carrier of X-linked HED is reported. Materials and Methods: Ovarian stimulation and assisted reproduction procedures were performed in a private academic medical center. PGT for a novel c.707-1G>A (rs886039466) mutation in EDA gene and chromosomal aneuploidies was performed by massive parallel and Sanger sequencing. Results: In the first PGT, the transfer of two blastocysts did not result in a pregnancy. An accumulative stimulation approach was decided to improve pregnancy chances for a second PGT procedure. Three ovarian stimulations were performed and 10 blastocysts coming from fresh and vitrified oocytes were genetically analyzed. A single embryo transfer produced a healthy non-carrier euploid girl. Discussion: PGT combining aneuploidy and mutation analyses is an alternative for female carriers of X-linked and other Mendelian disorders in Latin-American countries. In the era of genomic and personalized medicine, medically assisted reproduction techniques, such as PGT, are shifting from only infertility to preventive genetics.

Birth after human chorionic gonadotropin-primed oocyte in vitro maturation and fertilization with testicular sperm in a normo-ovulatory patient.

In this report, we present a case of in vitro maturation (IVM) with surgical retrieved testicular sperm in a normo-ovulatory female. Human chorionic gonadotropin-primed IVM, testicular biopsy for sperm retrieval and intracytoplasmic sperm injection with fresh sperm were performed. Fourteen cumulus-oocyte complexes were obtained in germinal vesicle or metaphase I stage, eight oocytes reached metaphase II, seven presumptive zygotes were obtained, and three cleavage stages embryos in day 2 were transferred producing a singleton pregnancy. A single healthy newborn was obtained. Our results suggest that IVM may be an alternative for in vitro fertilization in normo-ovulatory women even if surgical retrieval of sperm is needed. Further research is required to depict contributing factors to the success of IVM in indications different from polycystic ovaries syndrome and the role of male gamete.

A human reproductive approach to the study of infertility in chimpanzees: An experience at Leon's Zoological Park, Mexico.

Great apes are mammals close to humans in their genetic, behavioral, social and evolutionary characteristics and new genomic information is revolutionizing our understanding of evolution in primates. However, all these species are endangered. While there are many global programs to protect these species, the International Union for Conservation of Nature (IUCN) projects that in a near future the wild populations will decrease significantly. Nowadays, the relevance of captive populations of great apes is becoming critical for research and understanding of pathophysiology of diseases. In this report, the evaluation of infertility in a group of captive chimpanzees maintained at Leon's Zoological Park using a human infertility protocol is described. Our results suggested that infertility in this group was due to low hormonal levels and sperm alterations in the male characterized by hormonal assessment and a sperm sample obtained by electroejaculation and cryopreserved using human protocols. In the females, it was demonstrated that it is possible to follow the follicular cycle using non-invasive methods based on morphological changes in genitalia, detection of blood in urine and measurement of hormones in saliva samples; concluding that fertility in females was normal. Also, we demonstrate that human artificial insemination procedures may be applied. Our human approach was successful in finding the infertility cause in this group of captive chimpanzees. In countries with limited resources, collaboration of zoos with human infertility clinics can be beneficial for research and management of reproductive aspects of great apes.

Exome sequencing identifies a de novo frameshift mutation in the imprinted gene ZDBF2 in a sporadic patient with Nasopalpebral Lipoma-coloboma syndrome.

Nasopalpebral lipoma-coloboma syndrome (NPLCS, OMIM%167730) is an uncommon malformation entity with autosomal dominant inheritance characterized by the combination of nasopalpebral lipoma, colobomas in upper and lower eyelids, telecanthus, and maxillary hypoplasia. To date, no genetic defects have been associated with familial or sporadic NPLCS cases and the etiology of the disease remains unknown. In this work, the results of whole exome sequencing in a sporadic NPLCS patient are presented. Exome sequencing identified a de novo heterozygous frameshift dinucleotide insertion c.6245_6246 insTT (p.His2082fs*67) in ZDBF2 (zinc finger, DBF-type containing 2), a gene located at 2q33.3. This variant was absent in parental DNA, in a set of 300 ethnically matched controls, and in public exome variant databases. This is the first genetic variant identified in a NPLCS patient and evidence supporting the pathogenicity of the identified mutation is discussed. © 2016 Wiley Periodicals, Inc.

A rapidly progressive defective spermatogenesis in a Mexican family affected by spino-bulbar muscular atrophy.

Spino-bulbar muscular atrophy (SBMA) is an X-linked recessive adult progressive disorder affecting motor neurons. It is caused by a poly-glutamine tract expansion in the androgen receptor (AR) which generates protein aggregates that cannot be processed by proteasomes. A secondary mild androgen resistance is developed by AR dysfunction and patients present endocrine abnormalities including gynecomastia and poor function of testosterone in tissues; however, normally they are fertile. In this report we describe a Mexican family with three affected brothers with primary infertility caused by a progressive impairment of spermatogenesis leading to azoospermia before 40 years of age. They presented common features associated to patients affected by SMBA, such as gynecomastia, high level of CPK, muscle cramps, fasciculations, muscle wastage, and impaired swallowing. Two intracytoplasmic sperm injection (ICSI) cycles were performed in one of the patients resulting in fertilization failure. Molecular analysis of AR gene exon 1 revealed 54 CAG repeats in DNA extracted from leukocytes in affected patients and 22 repeats in the fertile non-affected brother. Severe impaired spermatogenesis of rapid progression has not been associated before to SBMA. This is the first report of assisted reproduction techniques indicated by male infertility in patients with this rare disorder. Further studies are required to confirm the unusual result of intracytoplasmic sperm injection cycles. We discuss the implications and possible pathogenesis of these unique features of SBMA in this family.

Novel LIPA mutations in Mexican siblings with lysosomal acid lipase deficiency.

Lysosomal acid lipase (LAL) deficiency is an under-recognized lysosomal disease caused by deficient enzymatic activity of LAL. In this report we describe two affected female Mexican siblings with early hepatic complications. At two months of age, the first sibling presented with alternating episodes of diarrhea and constipation, and later with hepatomegaly, elevated transaminases, high levels of total and low-density lipoprotein cholesterol, and low levels of high-density lipoprotein. Portal hypertension and grade 2 esophageal varices were detected at four years of age. The second sibling presented with hepatomegaly, elevated transaminases and mildly elevated low-density lipoprotein and low high-density lipoprotein at six months of age. LAL activity was deficient in both patients. Sequencing of LIPA revealed two previously unreported heterozygous mutations in exon 4: c.253C>A and c.294C>G. These cases highlight the clinical continuum between the so-called Wolman disease and cholesteryl ester storage disease, and underscore that LAL deficiency represents a single disease with a degree of clinical heterogeneity.

Acro-spondylo-pubic dysostosis associated with cataracts, microcephaly, and normal intelligence.

We report on an adult male with normal intelligence who exhibited an unusual combination of microcephaly, dysostoses of limbs, vertebrae, patellae, and pubic bone, camptodactyly of all fingers, and syndactyly of toes, absent nails on thumbs and some fingers, bilateral cataract, cryptorchidism, polythelia, and nipple-like skin pigmentations of shoulders and upper back. We have been unable to find a description of a similar combination of manifestations in literature. The cause of the anomalies remains unknown.

Clinical and genetic characteristics of mexican patients with juvenile presentation of niemann-pick type C disease.

Niemann-Pick type C disease (NPC) is a rare lysosomal disease with a protean presentation, ranging from a fatal neonatal course with visceromegaly to an adult presentation with only neurological or psychiatric symptomatology. In this report we describe the genetic and clinical characteristics of 3 Mexican patients from different families with juvenile presentation of NPC. Clinical examination, imaging of central nervous and gastrointestinal system, and EEG were performed. Genetic studies include sequencing and deletion/duplication analysis of NPC1 and NPC2 genes. All patients presented with cognitive impairment, ataxia, and supranuclear vertical gaze palsy; one case had gelastic cataplexy. Also they developed epilepsy and cortical atrophy and two patients had thinning of corpus callosum. The 3 patients were compound heterozygotes for NPC1 sequence variants, including 5 missense and 1 nonsense mutations: p.P1007A and p.F1087L in Case 1; p.Q921P and p.G992R in Case 2; and p.R348∗ and p.V1165M in case 3. Mexican patients with juvenile NPC presented with a variable clinical phenotype and compound heterozygosity. This suggests a relative high frequency of mutation carriers as it is reported for European population. Consequently, clinicians should consider NPC as a diagnosis possibility in any adolescent or young adult patient with juvenile dementia and/or ataxia, even in absence of gelastic cataplexy and supranuclear vertical gaze palsy.

[Genetic variants associated to male infertility in Mexican patients]. / Variantes genéticas asociadas con infertilidad masculina en pacientes mexicanos.

Recently Mexican Federation of Obstetrics and Gynecology Colleges (Federación Mexicana de Colegios de Obstetricia y Ginecologia, FEMECOG) published the Mexican guideline forthe management of male infertility, which suggests performing genetic laboratory tests as part of diagnosis and management of infertile patients and states that these should receive genetic counseling. This paper reviews the genetic approach proposed by Mexican guideline. A systematic review of medical literature was performed in Pubmed and Web of Knowledge from 1980 to 2012 in order to find reports of genetic variants associated to male infertility in Mexican patients. Also it is discussed the current knowledge of these variants, their clinical implications and finally the guidelines and recommendations for their molecular diagnosis. Most genetic variants in Mexican infertile patients are chromosome abnormalities. In relation to other variants there is only a report of Y chromosome microdeletions, repeated CAG in androgen receptor and more common mutations in CFTR, and other article reporting mutations in CFTR in patients with congenital absence of vas deferens. Little is known about the genetics of Mexican infertile patients apart from chromosome abnormalities. However, the contribution of genetics as etiology of male infertility is taking more relevance and currently the consensual management of infertile male should include the screening of genetic background. This review pretends to be a quick guide for clinicians who want to know about reports of genetic variants related to male infertility in Mexican population and how to approach their diagnosis.

Nasopalpebral lipoma-coloboma syndrome: clinical, radiological, and histopathological description of a novel sporadic case.

Nasopalpebral lipoma-coloboma syndrome is an extremely uncommon autosomal dominant condition characterized by congenital upper eyelid and nasopalpebral lipomas, colobomata of upper and lower eyelids, telecanthus, and maxillary hypoplasia. A few familial and sporadic cases of this malformation syndrome have been previously reported. Here, the clinical, radiological, and histopathological features of a sporadic Mexican patient with the nasopalpebral lipoma-coloboma syndrome are described. To our knowledge, this is the first time that craniofacial 3D computed tomography imaging was used for a detailed assessment of the facial lipoma.

Mucopolysaccharidosis type II in a female carrying a heterozygous stop mutation of the iduronate-2-sulfatase gene and showing a skewed X chromosome inactivation.

We report a Mexican girl showing the full blown clinical picture of mucopolysaccharidosis type II (MPSII). Iduronate-2-sulfatase (IDS) activity was low and she carried a heterozygous de novo c.1327C>T transition in exon 9, that changes codon 443 for a premature stop (TGA; p.Arg443(*)). Analysis of X-chromosome inactivation in androgen receptor (AR) locus showed a highly skewed ratio of 92:8 suggesting a functional hemizygosity with dominant expression of the mutant IDS and explaining the disease manifestation. This is one of the rare cases of females affected by MPSII due to the combined effect of a skewed X-chromosome inactivation and a de novo IDS mutation. We recommend that clinicians should consider the diagnosis of MPSII even in a girl without positive family history for this condition.

Y chromosome microdeletions in Mexican males of couples with idiopathic recurrent pregnancy loss.

AIM: To analyze the presence of Y chromosome microdeletions in males of Mexican couples with idiopathic recurrent pregnancy losses (RPL). METHODS: Seventy-one males from couples with RPL and 66 fertile males as controls were studied. DNA was isolated from peripheral lymphocytes and used to run multiplex polymerase chain reactions. Regions AZFa (sY84, sY86), AZFb (sY127, sY134) and AZFc (sY254, sY255) of the Y chromosome were analyzed according to valid guidelines recommended by the European Academy of Andrology and the European Molecular Genetics Quality Network. Also, the sequence tagged sites (STSs): DYS262 (sY67), DYS220 (sY129), DYF85S1 (sY150), DYF86S1 (sY152) and DYF87S1 (sY153) were included in order to analyze STSs previously reported as deleted. A power analysis to support our simple size was performed. RESULTS: Results show an absence of Y chromosome microdeletions in males of couples with RPL and controls with an acceptable statistical power. CONCLUSION: The study did not show an association of recurrent pregnancy loss and Y chromosome microdeletions in Mexican male partners. Based on the results, the study of Y chromosome microdeletions in couples with RPL is not considered clinically relevant.

[Prevention of mitochondrial diseases: a hope through assisted reproductive technologies]. / Prevención de enfermedades mitocondriales: una esperanza a través del uso de técnicas de reproducción asistida.

Mitochondrial diseases are a heterogenic and poorly studied group of diseases, considered serious in most cases and currently without treatment. Although assisted reproduction proposed strategies to prevent them, such as pre-implantation genetic diagnosis, these techniques are not sufficiently successful. However, the recent publication of two assistedreproduction techniques ­ meiotic spindle transfer in nonhuman primates and pronuclear transfer in humans ­ generate a clear ray of hope for the prevention of these diseases. This review analyzes the characteristics and meaning of these new findings and their future clinical implications.

Mining the Leishmania genome for novel antigens and vaccine candidates.

Leishmaniasis is a neglected disease with an estimated 12 million infected people. The recent completion of the sequencing of the Leishmania major genome has opened opportunities for the identification of targets for vaccine development. We present here the first attempt at identifying novel vaccine candidates by whole genome analysis. We predicted CD8(+) T cell epitopes from the L. major proteome and validated in vivo in mice the immunogenicity of some of the best predicted epitopes. Consensus epitope predictions from 8272 annotated protein sequences with 5-8 different algorithms allowed the identification of 78 class I CD8(+) epitopes. BALB/c mice were immunized with 26 synthetic peptides corresponding to the most likely epitopes. Fourteen (54%) resulted immunogenic, with eight being strong inducers of T cell IFNgamma production. None of the proteins from which the epitopes are derived are differentially expressed, only two may be surface proteins, eight have putative enzymatic, and metabolic activities. These epitopes and proteins represent new antigen candidates for further studies. While pathogen genomes have not yet delivered their full promise in terms of human health applications, our study opens the way for extensive genome mining for antigen identification and vaccine development against Leishmania and other pathogens.