Mutational spectrum of the iduronate-2-sulfatase gene in Mexican patients with Hunter syndrome.

OBJECTIVE: Hunter syndrome, or mucopolysaccharidosis type II (MPS II), is caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS), which is responsible for degrading heparan and dermatan sulfate. The IDS gene is located on chromosome Xq28; pathological variants in this gene mostly consist of missense mutations and small and larger deletions, which produce different phenotypes. However, there is only one record in our population concerning the molecular mechanism of this disease; a genotype-phenotype description is not available. PATIENTS AND METHODS: There were included 24 unrelated male patients; clinical features were recorded at a database, fluorometric IDS enzyme activity testing was done for each individual, followed by Sanger sequencing to identify mutations. RESULTS: The mutational spectrum was found in 16 out of 24 Mexican patients with MPS II, and its range of phenotypes was described. The most frequent variants were of the missense type. The most affected exons were exon 3 (c.275T>G, c.284_287del, c.325T>C), exon 8 (c.1035G>C, c.550G>A), exon 9 (c.1403G>C, c.1229_1229del), and exon 7 (c.979A>C; this variant has not been previously reported). Exon 5 (c.438C>T, a non-pathogenic variant) was the least frequent. It was also found that the most severely affected patients were those with large deletions (2 out of 24) [rsaIDS: IDSP1 (P164)x0, FMR1, AFF2 (P164)x2] involving genes and pseudogenes. We found 2 patients with a synonymous mutation in exon 4. CONCLUSIONS: Our results confirmed reports in the literature, since the most frequent variants were reported in exons 3 and 8. However, this result varies from one previous report in our population, which mentions large deletions and rearrangements as the most frequent alterations, since complex rearrangements were not found. According to what has been previously found, the most severely affected patients are those in which a whole gene has been deleted.

"Evaluation of four genes associated with primary ovarian insufficiency in a cohort of Mexican women".

PURPOSE: Primary ovarian insufficiency (POI) is a clinical condition observed in women younger than 40 years of age, characterized by amenorrhea, hypoestrogenism, high levels of follicle-stimulating hormone (FSH), and infertility. Mutations in some master regulators of the development, maturation, and maintenance of ovarian follicles such as BMP15, FSHR, FOXL2, and GDF9 have been suggested as etiological factors in the development of POI. The aim of this study, the first in the Mexican population, is to evaluate the presence of mutations or polymorphisms in these four candidate genes. METHODS: In a sample of 20 Mexican patients with idiopathic POI, we looked for and analyzed genetic variants in BMP15, FSHR, FOXL2, and GDF9 genes. RESULTS: We observed two polymorphisms: a coding change, c.919G>A (p.Ala307Thr), in the FSHR gene and a synonymous variant, c.447C>T (p.Thr149Thr), in the GDF9 gene. These two variants have been reported previously as polymorphisms (rs6165 and rs254286, respectively). We observed no significant difference associated with POI in the patients when compared with a healthy control group (p > 0.05). Also, no exonic variants were found for the genes BMP15 and FOXL2 in the individuals tested. CONCLUSIONS: The lack of association of the evaluated genes in this sample of Mexican women is consistent with the complex genetic etiology of POI that is observed across cohorts studied thus far.

Mexican consensus on lysosomal acid lipase deficiency diagnosis. / Consenso mexicano sobre el diagnóstico de la deficiencia de lipasa ácida lisosomal.

INTRODUCTION: Lysosomal acid lipase deficiency (LAL-D) causes progressive cholesteryl ester and triglyceride accumulation in the lysosomes of hepatocytes and monocyte-macrophage system cells, resulting in a systemic disease with various manifestations that may go unnoticed. It is indispensable to recognize the deficiency, which can present in patients at any age, so that specific treatment can be given. The aim of the present review was to offer a guide for physicians in understanding the fundamental diagnostic aspects of LAL-D, to successfully aid in its identification. METHODS: The review was designed by a group of Mexican experts and is presented as an orienting algorithm for the pediatrician, internist, gastroenterologist, endocrinologist, geneticist, pathologist, radiologist, and other specialists that could come across this disease in their patients. An up-to-date review of the literature in relation to the clinical manifestations of LAL-D and its diagnosis was performed. The statements were formulated based on said review and were then voted upon. The structured quantitative method employed for reaching consensus was the nominal group technique. RESULTS: A practical algorithm of the diagnostic process in LAL-D patients was proposed, based on clinical and laboratory data indicative of the disease and in accordance with the consensus established for each recommendation. CONCLUSION: The algorithm provides a sequence of clinical actions from different studies for optimizing the diagnostic process of patients suspected of having LAL-D.

Clinical features of Mexican patients with Mucopolysaccharidosis type I.

Mucopolysaccharidosis type I (MPS-I) is an autosomal recessive lysosomal storage disorder caused by a deficiency or absence of α--iduronidase, which is involved in the catabolism of glycosaminoglycans (GAGs). This deficiency leads to the accumulation of GAGs in several organs. Given the wide spectrum of the disease, MPS-I has historically been classified into 3 clinical subtypes - severe (Hurler syndrome), intermediate (Hurler-Scheie syndrome), and mild (Scheie syndrome) - none of which is determined by residual enzyme activity. Eleven Mexican patients with MPS-I from northwestern México were evaluated. Diagnoses were confirmed through quantification of GAGs in urine and enzyme assay for α--iduronidase. Regardless of phenotype, all patients had various degrees of infiltrated facies, short stature, dysostosis multiplex, joint contractures, and corneal opacity typical of the disease. A better understanding of the spectrum of this disease can assist in diagnosis, treatment, and improvement in the quality of life for these patients.

Molecular thrombophilic profile in Mexican patients with idiopathic recurrent pregnancy loss.

Idiopathic recurrent pregnancy loss (IRPL) is defined by three or more consecutive miscarriages occurring before the twentieth week of gestation as a result of unidentified etiological factors. The results of previous studies have indicated that prothrombotic factors play a pathogenic role in early and late pregnancy. This study aimed to identify inherited prothrombotic and hypofibrinolytic risk factors in Mexican-Mestizo patients with IRPL. Fifty-six women with IRPL and 50 control women with at least two full-term pregnancies and no history of RPL were included in this case-control study. Four prothrombotic (F5 G1691A, F2 G20210A, MTHFR C677T-A1298C) and one hypofibrinolytic (PAI1 4G/5G) restricted fragment length polymorphisms were subjected to molecular analysis. In the case of hypofibrinolytic ACE Ins/Del (I/D), identification was performed by direct PCR. The independent risk correlated with the presence of polymorphisms in IRPL patients was estimated using odds ratio (OR) with a 95% confidence interval (CI). MTHFR 677TT was the most frequent prothrombotic factor in the IRPL group (23%), followed by the compound-heterozygous C677T-A1298C (16%) and heterozygous F2 20210GA (3.6%). The heterozygous ACE I/D (62%) was the main hypofibrinolytic risk factor of IRPL, followed by the homozygote PAI1 4G/4G (18%). The ACE I/D polymorphism was the only significantly different factor among the cases and controls. The dominant genetic model D/D+I/D vs I/I showed an OR (95%CI) of 2.89 (1.22-6.89) and P = 0.019 in Mexican-Mestizo women. The results of this study support an association between the ACE I/D polymorphism and IRPL risk in a Mexican population.

SEVERE HYDROCEPHALUS, KIDNEY AND SKELETAL ANOMALIES IN A FEMALE PATIENT WITH MILD NEUROLOGICAL ALTERATIONS.

The appearance of untreated severe hydrocephalus with long-term survival is infrequent; here we report a case with these characteristics, mild neurological alterations and kidney and skeletal anomalies. A female patient showed severe hydrocephalus (initially mistaken with hydranencephaly) at 4 years old and left kidney ectopia (initially mistaken with renal agenesis); however, she was derived to the neurology service until she was 12 years old, when she began to present migraine and seizures. At 13 years old the patient was diagnosed with arrested hydrocephalus secondary to aqueduct stenosis, and the seizures worsen thereafter from atonic seizures to complex partial seizures (at 14 years old), presenting generalized seizures at 15 years old. At 17 years old, the seizures were more frequent despite the anticonvulsant treatment and also presented automations, she was also diagnosed with genu recurvatinn and scoliosis. The seizures finally diminished and partially controlled at 19 years old. Despite a cerebral mantle < 2.0 cm at the computer tomography, the patient always presented a satisfactory intellectual development. In this case, the relatively good and long evolution of the severe hydrocephalus is probably related with the late-onset of the disease that permitted a better development of the brain; however, the worsening of the seizures after the hydrocephalus arrested, suggests that arrest is not necessarily associated with a compensation and better evolution of the disease, at least at the beginning of the process. The presence of kidney ectopia and skeletal alterations did not associate with a known genetic disease, however a possible inheritance mechanism is not discarded.

Mutational screening of CHX10, GDF6, OTX2, RAX and SOX2 genes in 50 unrelated microphthalmia-anophthalmia-coloboma (MAC) spectrum cases.

BACKGROUND/AIMS: Microphthalmia-anophthalmia-coloboma (MAC) are congenital eye malformations causing a significant percentage of visually impairments in children. Although these anomalies can arise from prenatal exposure to teratogens, mutations in well-defined genes originate potentially heritable forms of MAC. Mutations in genes such as CHX10, GDF6, RAX, SOX2 and OTX2, among others, have been recognised in dominant or recessive MAC. SOX2 and OTX2 are the two most commonly mutated genes in monogenic MAC. However, as more numerous samples of MAC subjects would be analysed, a better estimation of the actual involvement of specific MAC-genes could be made. Here, a comprehensive mutational analysis of the CHX10, GDF6, RAX, SOX2 and OTX2 genes was performed in 50 MAC subjects. METHODS: PCR amplification and direct automated DNA sequencing of all five genes in 50 unrelated subjects. RESULTS: Eight mutations (16% prevalence) were recognised, including four GDF6 mutations (one novel), two novel RAX mutations, one novel OTX2 mutation and one SOX2 mutation. Anophthalmia and nanophthalmia, not previously associated with GDF6 mutations, were observed in two subjects carrying defects in this gene, expanding the spectrum of GDF6-linked ocular anomalies. CONCLUSION: Our study underscores the importance of genotyping large groups of patients from distinct ethnic origins for improving the estimation of the global involvement of particular MAC-causing genes.

Apolipoprotein E genotypes in Mexican patients with Parkinson's disease.

BACKGROUND: The association of the apolipoprotein (Apo E) -epsilon4 allele to neurodegenerative diseases such as Parkinson's disease (PD) has been analyzed in several studies. This association has been identified by amyloid deposits and neurofibrillary tangles in the brains of patients with neurodegenerative diseases. METHOD: In this study the possible relationship between Apo E alleles and PD patients was analyzed in 105 patients with PD and 107 healthy controls from a Mexican population. RESULTS: Allele analysis in PD vs. controls was: epsilon2 in 6% and 2.3%, respectively; epsilon3 in 73% and 88.3%; and epsilon4} in 21% and 9.4%. The epsilon3 allele showed a protective risk effect with an Odds ratio (OR) of 0.36 (95%CI 0.20-0.61) and p < 0.05; contrary results were observed for the epsilon4 allele, which showed an increased risk for PD, with an OR of 2.57(95% CI 1.42-4.79) and p < 0.05. Upon multivariate analysis showed PD risk was evident in patients who were carriers of the genotype epsilon3/epsilon4; age group (fifty or more years) and had exposure to pesticides and solvents (p < 0.05). CONCLUSIONS: The epsilon3/epsilon3}; epsilon3/epsilon4 genotypes of the Apo E, were positively associated with sporadic PD.

Association of the 677C -->T polymorphism in the MTHFR gene with colorectal cancer in Mexican patients.

The 5,10-methyl-tetrahydrofolate reductase (MTHFR) enzyme plays a critical role in folate and homocysteine metabolism, and its gene, MTHFR, displays common genetic polymorphisms that influence its activity. Clinical implications of MTHFR polymorphisms have been reported for several diseases, including a variety of solid tumors such as colorectal cancer (CRC). Here, the role of the 677C -->T polymorphism of MTHFR was evaluated by genotyping 369 patients and 170 healthy controls from the Mexican population. The observed genotype frequencies for the controls and patients, respectively, were: 18.8% and 32% for 677TT; 34.7% and 34% for 677CC; 46.4% and 34% for 677CT. The odds ratio (OR) was 2.0 (95% confidence intervals CI; 1.3-3.3) (p<0.05). The data suggested that the 677C -->T polymorphism in MTHFR contributes significantly to the risk of CRC susceptibility in the Mexican population.

A missense mutation, p.V132G, in the X-linked spermine synthase gene (SMS) causes Snyder-Robinson syndrome.

Snyder-Robinson syndrome (SRS, OMIM 309583) is a rare X-linked syndrome characterized by mental retardation, marfanoid habitus, skeletal defects, osteoporosis, and facial asymmetry. Linkage analysis localized the related gene to Xp21.3-p22.12, and a G-to-A transition at point +5 of intron 4 of the spermine synthase gene, which caused truncation of the SMS protein and loss of enzyme activity, was identified in the original family. Here we describe another family with Snyder-Robinson syndrome in two Mexican brothers and a novel mutation (c.496T>G) in the exon 5 of the SMS gene confirming its involvement in this rare X-linked mental retardation syndrome.

Metaphyseal chondrodysplasia, upper limb mesomelia and normal height (mesomelic dysplasia camera type): second report in a Mexican patient.

Mesomelic dysplasias (MD) are a group of skeletal disorders with exclusive or predominant shortness of the middle segment of the limbs, with or without involvement of the hands/feet or other body parts. Short stature is a usual consequence due to involvement of the lower limbs. In 2003, Camera and Camera reported an unusual upper limb MD with normal stature and radiological evidence of long bone metaphyseal dysplasia. Here, we describe a Mexican patient showing a similar clinical and radiological phenotype, in addition to esophageal atresia, palpebral ptosis and slight lower limb asymmetry. This represents the second case reported in the literature, corroborating the existence of this rare entity.

SED-brachydactyly and distinctive speech: report of two new cases.

We describe two unrelated patients and the mother of one of them showing clinical and radiological features as those previously described in the spondyloepiphyseal dysplasia-brachydactyly and distinctive speech (SED-BDS, also named Fantasy Island syndrome or Tattoo dysplasia) clinically characterized by short stature with acral shortness, distinctive face, mild blepharophimosis, upslanted palpebral fissures, abundant eyebrows and eyelashes, thick and abundant hair and coarse voice; and radiologically by brachymetacarpalia, brachymetatarsalia and brachyphalangia of all fingers and toes, short and broad long bones with normal morphology and small pelvis. The clinical and radiological features present in mother and son suggest a probable autosomal dominant mode of inheritance and variable expressivity.

High-resolution molecular characterization of the HLA class I and class II in the Tarahumara Amerindian population.

We describe for the first time the high-resolution profiling of HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 in a culturally and geographically distinct Mexican ethnic group, the Tarahumaras. The alleles most frequently found by reference strand-mediated conformational analysis in this population were for class I: HLA-A*240201, *020101/09, *0206, *310102, *680102; HLA-B*4002, *1501, *510201, *3501/02/03, *4005, *4801; HLA-Cw*0304, *0801, *0102, *040101; and for class II: HLA-DRB1*080201, *1402, *040701; HLA-DQB1*0402, *0301, *0302/07; HLA-DPB1*0402, *0401, *020102. In addition, a novel allele, HLA-A*0257, was found. Based on comparison of presently known HLA-DRB1 and -DQB1 allele frequencies in Amerindian groups and worldwide populations, the Tarahumaras are unexpectedly more related to the geographically and linguistically distant Aymara and Terena Amerindian groups than they are to neighbouring tribes.

Familial iridogoniodysgenesis and skeletal anomalies: a probable new autosomal recessive disorder.

Three sibs with congenital glaucoma, skeletal anomalies, and peculiar facial appearance were studied. At birth, enlarged eyes and corneae were present in the proposita and her two brothers due to congenital glaucoma secondary to iridogoniodysgenesis (IGD). The purpose of this article is to describe the second familial case with IGD and skeletal anomalies as the family previously described by García-Cruz et al. in 1990, corroborating this new distinct dysmorphic syndrome with probable autosomal recessive inheritance.

Second female case of Myhre syndrome.

Myhre syndrome is a rare disorder characterized by low birthweight, short stature, mental retardation, facial dysmorphism (blepharophimosis, midfacial hypoplasia, prognathism), heart anomalies, muscle hypertrophy, decreased joint mobility and deafness. To date 11 male cases and only one female case have been reported. This paper describes the second female case and compares the clinical and radiological findings between female and male patients.

Complete achromatopsia associated with skeletal anomalies: a new autosomal recessive syndrome.

Complete achromatopsia associated with skeletal anomalies: a new autosomal recessive syndrome: Achromatopsia or rod monochromatism is the complete absence of color discrimination, with an estimated frequency of 1 in 100,000. To date the McKusick Catalogue includes more than 10 entities related to Achromatopsia. This paper describes four Mexican sibs with a stationary rod monochromatism, associated with long fingers and toes, hypothenar and thenar hypoplasia and pes planus, suggesting a new genetic entity probably inherited in an autosomal recessive mode.

p63 gene analysis in Mexican patients with syndromic and non-syndromic ectrodactyly.

Ectrodactyly is a congenital limb malformation that involves a central reduction defect of the hands and/or feet which is frequently associated with other phenotypic abnormalities. The condition appears to be genetically heterogeneous and recently it has been demonstrated that mutations in the p63 gene, a homologue of the tumor suppressor gene p53, are the cause of at least four autosomal dominant genetic syndromes which feature ectrodactyly: ectrodactyly, ectodermal dysplasia, and facial clefting (EEC), split hand/split foot malformation (SHFM), limb-mammary syndrome (LMS), and acro-dermato-ungual-lacrimal-tooth syndrome (ADULT). In this study, genetic analysis of the p63 gene in a group of 13 patients with ectrodactyly (syndromic and isolated) was performed. Four patients with syndromic ectrodactyly had p63 heterozygous point mutations that affect the DNA binding domain of the protein. One of these subjects exhibited the typical features of EEC syndrome as well as ankyloblepharon being, to our knowledge, the first case combining these traits. This finding supports the view of a clinical overlap in this group of autosomal dominant syndromes caused by p63 mutations and demonstrates that there are exceptions in the previously established p63 genotype-phenotype correlation.

A novel HLA-A allele: A*0257.

A novel human leucocyte antigen-A*02 (HLA-A*02) allele was detected by reference strand-mediated conformation analysis (RSCA) of a DNA sample from a Tarahumara individual. Direct sequencing of HLA-A locus polymerase chain reaction products identified a mutation in one of the alleles. Cloning and sequencing confirmed the presence of a new allele, A*0257 which differed from A*0206 by two nucleotides at positions 355 and 362, inducing changes in residues 95 and 97, respectively, within the peptide-binding site. Those changes suggest that allele A*0257 may have resulted from an intralocus recombination event.