Luis E. Figuera

Effects of enzyme replacement therapy in Fabry disease--a comprehensive review of the medical literature.

Enzyme replacement therapy with α-galactosidase A has been used to treat Fabry disease since 2001. This article reviews the published evidence for clinical efficacy of the two available enzyme preparations. We focused on heart, kidney, and nervous system manifestations, which impact both quality of life and overall prognosis. A literature search was undertaken to identify prospective open or randomized controlled trials of enzyme replacement therapy in patients with Fabry disease published since 2001. To date, no definitive conclusion can be drawn from studies that have directly compared therapeutic responses between the two commercially available enzyme preparations. Significant clinical benefits of enzyme replacement therapy have been demonstrated, mainly in patients at an early phase of the disease, with beneficial effects on heart, kidneys, pain, and quality of life in treated patients. Incidence of antibodies against agalsidase alfa and agalsidase beta observed during major clinical studies suggests a greater antigenic response to agalsidase beta. Further studies are required to confirm the long-term clinical benefits of enzyme replacement therapy. More studies with female patients are needed as are investigations of early initiation of enzyme replacement therapy to determine the optimal time to start treatment to prevent irreversible organ damage. The value of adjunctive and supportive therapies should also be rigorously analyzed.

Therapeutic goals in the treatment of Fabry disease

Purpose: Fabry disease is a progressive multiorgan, multisystem disorder that is caused by a deficiency in the lysosomal enzyme α-galactosidase A. Serious renal, cardiac, and cerebrovascular involvement are responsible for much of the morbidity and premature mortality associated with Fabry disease, and neuropathic pain, gastrointestinal problems, and hypohidrosis negatively affect quality of life of patients with Fabry disease. Fabry disease is X-linked, but women are often symptomatic and may be as severely affected as men.Methods: We propose a series of therapeutic and symptomatic goals for use in setting the expectations of enzyme replacement therapy and for assessing the response to enzyme replacement therapy in the treatment of Fabry disease.Results: Enzyme replacement therapy has been available since 2001 and has been associated with benefit in clinical trials, including stabilization of kidney function, improvement of cardiac structure and function, reduction in severity of neuropathic pain, and improvement in gastrointestinal involvement.Conclusions: The presentation of these therapeutic goals will aid in the evaluation of response to enzyme replacement therapy and be useful in establishing an overall management plan for individual patients.

Oral‐facial‐digital syndrome with fibular aplasia: a new variant

Figuera LE, Rivas F, Cantú JM. Oral‐facial‐digital syndrome with fibular aplasia: a new variant.

Inherited hypertrichoses: Inherited hypertrichoses

Hypertrichosis is a rare condition characterized by excessive growth of hair (terminal, vellus or lanugo) in areas of the body that are not predominantly androgen dependent, and it is independent of age, race or sex. It can be congenital, late‐onset, generalized, localized, inherited or acquired. More than 50 different OMIM entries related to hypertrichosis exist, few of them with a localized gene locus or with a candidate gene. The review of generalized hypertrichoses from a historical point of view, including a review of their clinical and genetic features, shows heterogeneity with at least nine different entities. A short analysis of other forms of hypertrichosis is presented.

Allele frequency distributions of six amp-FLPS (D1S80, APO-B, VWA, TH01, CSF1PO and HPRTB) in a Mexican population

Six amplified fragment length polymorphisms or Amp-FLPs, two VNTRs (D1S80 and APO-B) and four STRs (VWA, TH01, CSF1PO and HPRTB), were typed in a Mexican population of the Jalisco state by means of non-denaturing polyacrylamide gel electrophoresis (native PAGE) in standard gel units and silver staining. Genotype distribution was in agreement with Hardy-Weinberg expectations (HWE) for all six markers. Heterozygosity ranged from 70.6 to 83.5%, the cumulated chance of exclusion (CE) and power of discrimination (PD) were 99.4 and 99.99%, respectively. STRs and D1S80 allele frequency distributions (AFD) were similar (P > 0.05) to U.S. Hispanics, but different to U.S. Caucasians and African-Americans. APO-B exhibited similarities with White Brazilians, Spaniards, but differences (P < 0.05) with Amerindian and Black Brazilians.

The TP53 16-bp Duplication Polymorphism Is Enriched in Endometriosis Patients

Background/Aim: The TP53 tumor suppressor gene encodes the nuclear phosphoprotein p53, which plays an important role in cell cycle regulation, apoptosis, DNA repair and angiogenesis. The TP53 gene contains common genetic polymorphisms that influence gene activity. Clinical implications of TP53 polymorphisms have been reported for several diseases, including a variety of solid tumors and endometriosis. We evaluated the association of a TP53 duplication polymorphism with endometriosis. Methods: We evaluated the role of the TP53 16-bp duplication polymorphism by comparing the genotypes of 204 healthy women (controls with surgically excluded endometriosis) to the genotypes of 151 women with endometriosis in the Mexican population. Results: The observed genotype frequencies for controls and endometriosis patients were 0.5 and 5% for 16 bp+/+, 11 and 21% for 16 bp+/–, and 88.5 and 77% for 16 bp–/–, respectively. The odds ratio (OR) was 9.8 (95% CI 1.2–446.8; p = 0.01). The association was more evident when we compared the distribution of genotype 16 bp+/+ to genotype 16 bp+/–. In patients with moderate/severe endometriosis, the OR was 4.0 (95% CI 1.6–9.8; p = 0.003). Conclusion: Our data suggest that the 16-bp duplication polymorphism in TP53 contributes significantly to endometriosis susceptibility in the Mexican population.

Y-Chromosome Haplotypes for Six Short Tandem Repeats (STRs) in a Mexican Population

BACKGROUND Short tandem repeats (STRs) on the non-pseudoautosomal region of the Y-chromosome are DNA polymorphic markers able to solve special cases in legal medicine, for instance in paternity testing where the alleged father is not available, and in forensic situations, such as rape cases, where mixtures of male/female DNA are present. METHODS Six STR polymorphisms from the Y-chromosome (DYS19, DYS385, DYS389/I, DYS390, DYS391, and DYS393) were PCR-typed in 120 males from the northwest region of Mexico by means of native polyacrylamide gel electrophoresis and silver staining. RESULTS Allele frequencies were estimated for each STR. Their gene diversity ranged from 51.4% for DYS393 to 92.5% for DYS385. Mexican Y-STR allele distributions displayed similarity (p >0.05) with previously reported U.S. Hispanics for DYS19, DYS389/I, DYS390, DYS391, and DYS393. Although Mexicans showed the same modal allele for DYS385 (11/14; 24.4%) with regard to most European populations, differences in allele distributions were observed (p <0.01). The haplotype diversity and the male discriminatory capacity of this six-locus system were 99.3 and 84.1%, respectively. CONCLUSIONS This knowledge permits the effective use of these six Y-chromosome markers in legal medicine casework in the studied population. This STR-system offers a great potential to identify males and male-lineages, and can be used confidentially in paternity testing and forensic analysis in the Mexican population.

Intron 4 VNTR (4a/b) Polymorphism of the Endothelial Nitric Oxide Synthase Gene Is Associated with Breast Cancer in Mexican Women

The endothelial nitric oxide synthase (eNOS) gene plays an important role in several biological functions. Polymorphisms of the eNOS gene have been associated with cancer. It has been suggested that the VNTR 4 a/b polymorphism may affect the expression of eNOS and contributes to tumor promotion in the mammary gland. We examined the role of the eNOS4 a/b polymorphism by comparing the genotypes of 281 healthy Mexican women with the genotypes of 429 Mexican women with breast cancer (BC). The observed genotype frequencies for control and BC patients were 0.6% and 0.7% for a/a (polymorphic); 87% and 77% for a/a (wild type); and 12% and 22% for a/b respectively. We found that the odds ratio (OR) was 1.9, with a 95% confidence interval (95%CI) of 1.29-2.95, P = 0.001 for genotypes a/a-a/b, b/c. The association was also evident when comparing the distribution of the a/a-a/b genotypes in patients with high levels of glutamate-oxaloacetate transaminase (SGOT) (OR, 1.93; 95% CI, 1.14-3.28; P = 0.015); undergoing menopause with high levels of SGOT (OR, 2.0; 95% CI, 1.1-3.84); and with high levels of glutamic-pyruvic transaminase (SGPT) (OR, 3.5; 95% CI, 1.56-8.22). The genotypes a/a-a/b are associated with BC susceptibility in the analyzed samples from the Mexican population.

Distribution of CYP1A1⁎2A polymorphism in adult patients with acute lymphoblastic leukemia in a Mexican population

The effects of the CYP1A1*2A genotype on susceptibility to leukemia have received particular attention in recent years because this enzyme plays a central role in the activation of carcinogens. Several polymorphisms at the CYP1A1 locus have been identified and their genotypes appear to exhibit population frequencies that depend on ethnicity. We evaluated the role of the CYP1A1*2A genotype in adults with acute lymphoblastic leukemia (ALL) by genotyping 210 patients and 228 healthy controls from the Mexican population. The frequency of the CC genotype was 8% (18/228) in the control group and 42% (88/210) in ALL patients; the frequency of the CT genotype was 39% (89/228) and 29.5% (62/210), respectively; and that of the TT genotype was 53% (121/228) and 28.5% (60/210), respectively. The odds ratio was 8.4 (95% CI, 4.7-15.5; P < 0.001). These data indicate that the CYP1A1*2A genotype contributes significantly to susceptibility to adult ALL in a sample of the Mexican population.

Pure partial trisomy 6p due to a familial insertion (16;6)(p12;p21.2p23)

There have only been eight patients with 6p pure trisomy involving different segments: four cases resulted from a translocation or insertion and four were due to an intrachromosomal duplication. We report here the first postnatally ascertained patient with a pure 6p partial trisomy due to an interchromosomal insertion (16;6)(p12;p21.2p23)mat. This rearrangement was confirmed by fluorescent in situ hybridization (FISH) with whole chromosome 6 and 16 painting probes. The clinical findings in the present patient were similar to those observed in previous cases, including craniofacial dysmorphism, minor anomalies, and lack of severe anatomical defects; yet, the unspecificity of many of these features prevented us from delineating the 6p pure trisomy syndrome.