[Hereditary sensory and autonomic neuropathy type II A: early neurological and skeletal findings]. / Neuropatía sensitiva autonómica hereditaria tipo IIA: manifestaciones neurológicas y esqueléticas tempranas.

The hereditary sensory and autonomic neuropathies are genetic disorders characterized by the loss of sensation including pain, tactile and temperature. Its clinical and molecular features vary widely; the symptoms may begin from birth or be noticed in the first or second decade, with different types of complications of trauma to the extremities such as ulcers, mutilations and acral amputations. They are classified into six groups from I to VI, determined by the abnormality in eleven genes leading to phenotypic variations in the age of onset and the presence or absence of dysautonomia signs. With the exception of type I, all are autosomal recessive. The type II of these neuropathies is characterized by insensitivity to pain, heat and proprioception. We describe three members of a Mexican family with WNK1 gene mutation that caused hereditary neuropathy IIA.

Segregation analysis in X-linked ichthyosis: paternal transmission of the affected X-chromosome.

BACKGROUND: Steroid sulphatase (STS) deficiency has been described in a diversity of ethnic populations. The phenotype of STS deficiency, X-linked ichthyosis (XLI), is a genodermatosis characterized by dark scaly skin. About 90% of patients with XLI have complete deletion of the entire STS gene and flanking sequences. The variable number tandem repeats, on either side of the STS gene, appear to play an important role in these interstitial deletions due to nonallelic homologous recombination (NAHR). It is difficult to establish if this NAHR occurs between two chromosomes, between sister chromatids or between the same chromatid. OBJECTIVES: To identify the parental origin of the affected X-chromosome in seven unrelated sporadic cases of XLI. METHODS: Amplification of the regions from DXS89 to DXS1134 (telomeric-centromeric) including the 5' and 3' ends of the STS gene was performed through polymerase chain reaction. GeneScan analysis was performed using the DXS987, DXS8051 and DXS1060 markers located on the short arm of the X-chromosome. Fluorescence in situ hybridization analysis was performed with a digoxigenin-labelled cDNA STS probe. RESULTS: STS gene deletion in patients with XLI involved the sequences DXS1139 and DXF22S1. In five families segregation analysis showed paternal transmission of the affected X-chromosome in the XLI carrier. It was not possible to determine the parental origin of the affected X-chromosome in two families. CONCLUSIONS: These data strongly suggest that STS gene deletion occurred in the male meiosis probably due to an intrachromosomal event, recombination between S232 sequences on the same DNA molecule, or during the process of DNA replication.

Analysis of the VCX3A, VCX2 and VCX3B genes shows that VCX3A gene deletion is not sufficient to result in mental retardation in X-linked ichthyosis.

BACKGROUND: X-linked ichthyosis (XLI), an inborn error of metabolism, is due to steroid sulphatase (STS) deficiency. Most patients with XLI harbour complete deletion of the STS gene and flanking sequences. The presence of low copy number repeats on either side of the STS gene seems to have a major role in the high frequency of these deletions. Some patients with XLI with terminal deletions of Xp22.3 involving marker DXS1139 and the STS gene show mental retardation (MR); VCX3A is the only gene located on this critical region. OBJECTIVES: To analyse the VCX3A, VCX, VCX2 and VCX3B genes in 80 unrelated Mexican patients with XLI with normal intelligence. METHODS: STS activity was measured in the leucocytes using 7-[3H]-dehydroepiandrosterone sulphate as a substrate. Amplification of the regions from telomeric DXS89 to centromeric DXS1134 including both extremes of the STS and the VCX3A, VCX, VCX2 and VCX3B genes was performed using polymerase chain reaction. RESULTS: No STS activity was detected in the patients with XLI (0.00 pmol mg(-1) protein h(-1)). We observed two different deletion patterns: the first group included 62 patients with deletion of VCX3A and VCX genes. The second group included 18 patients with breakpoints at several regions on either side of the STS gene not including the VCX3A gene. CONCLUSIONS: These data indicate that more complex mechanisms, apart from possible VCX3A gene participation, are occurring in the genesis of MR in XLI, at least in the sample of Mexican patients analysed.

Molecular analysis of the CYP1B1 gene: identification of novel truncating mutations in patients with primary congenital glaucoma.

BACKGROUND: Mutations and polymorphisms have been identified in the CYP1B1 gene; while mutations that affect the conserved core structures of cytochrome P4501B1 result in primary congenital glaucoma (PCG), mutations in other regions hold the potential to define differences in estrogen metabolism. In the present study, we analyzed the CYP1B1 gene in Mexican patients with PCG and described four novel mutations. MATERIALS AND METHODS: The sample included 12 nonrelated cases with PCG. Analysis of coding regions of the CYP1B1 gene was performed through PCR and DNA sequencing analysis from genomic DNA. RESULTS AND DISCUSSION: Molecular analysis of the CYP1B1 gene showed the following molecular defects: (1) a novel single-base pair deletion within codon 370 (1454delC) that produces a substitution of leucine instead of proline and a premature stop codon 57 amino acids after the last original amino acid; this family also harbored a novel polymorphic variant of the cytochrome P4501B1 with six single-nucleotide polymorphisms (142C-->G; 355G-->T; 729G-->C; 4326C-->G; 4360C-->G and 4379C-->T); (2) a novel single-base pair deletion within codon 277 (1176delT) that results in a premature stop codon; (3) a novel single-base pair deletion within codon 179 (880delG) that produces a substitution of arginine instead of alanine and a premature stop codon 17 amino acids downstream from the last original amino acid, and (4) a duplication (or insertion) of ten base pairs within codon 404 (1556dupATGCCACCAC) that results in a premature stop codon 26 amino acids after the last original amino acid. We also observed in 2 nonrelated patients a deletion of 13 bp (1410_1422delGAGTGCAGGCAGA) previously reported for other populations. CONCLUSION: We reported four novel mutations and a novel polymorphic variant in the CYP1B1 gene in PCG in the Mexican population; it has important implications in diagnosis and genetic counseling.

Deletion pattern of the STS gene in X-linked ichthyosis in a Mexican population.

BACKGROUND: X-linked ichthyosis (XLI) is an inherited disorder due to steroid sulfatase deficiency (STS). Most XLI patients (>90%) have complete deletion of the STS gene and flanking sequences. The presence of low copy number repeats (G1.3 and CRI-S232) on either side of the STS gene seems to play a role in the high frequency of these interstitial deletions. In the present study, we analyzed 80 Mexican patients with XLI and complete deletion of the STS gene. MATERIALS AND METHODS: STS activity was measured in the leukocytes using 7-[(3)H]-dehydroepiandrosterone sulfate as a substrate. Amplification of the regions telomeric-DXS89, DXS996, DXS1139, DXS1130, 5' STS, 3' STS, DXS1131, DXS1133, DXS237, DXS1132, DXF22S1, DXS278, DXS1134-centromeric was performed through PCR. RESULTS: No STS activity was detected in the XLI patients (0.00 pmoles/mg protein/h). We observed 3 different patterns of deletion. The first two groups included 25 and 32 patients, respectively, in which homologous sequences were involved. These subjects showed the 5' STS deletion at the sequence DXS1139, corresponding to the probe CRI-S232A2. The group of 32 patients presented the 3' STS rupture site at the sequence DXF22S1 (probe G1.3) and the remaining 25 patients had the 3' STS breakpoint at the sequence DXS278 (probe CRI-S232B2). The third group included 23 patients with the breakpoints at several regions on either side of the STS gene. No implication of the homologous sequences were observed in this group. CONCLUSION: These data indicate that more complex mechanisms, apart from homologous recombination, are occurring in the genesis of the breakpoints of the STS gene of XLI Mexican patients.