[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.

Satoyoshi syndrome with unusual skeletal abnormalities and parental consanguinity.

Satoyoshi syndrome (SS) (OMIM 600705) is a rare multisystemic disorder of unknown etiology characterized by progressive painful intermittent muscle spasm, alopecia universalis, diarrhea, short stature, amenorrhea, and secondary skeletal abnormalities mimicking a metaphyseal chondrodysplasia. To date all reported cases have been sporadic. We describe a 26-year-old Mexican woman, a product of consanguineous parents with clinical characteristics of SS. Our patient, also showed skeletal anomalies not previously reported that seems to be a coincidental finding.

Two different PABPN1 expanded alleles in a Mexican population with oculopharyngeal muscular dystrophy arising from independent founder effects.

BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is a late onset hereditary myopathy of autosomal dominant transmission characterised by ptosis, dysphagia and limb weakness. The disease is caused by short heterozygous expansions of a (GCN)(10) triplet located in the first exon of the PABPN1 gene at chromosome 14q11.1. Most affected individuals from North America and Europe carry a mutant (GCN)(13) allele. Although evidence for a founder mutation effect has been shown in several populations with OPMD, analysis of large groups of patients from different ethnic backgrounds will help to identify the relative contribution of each allele to the disease and a possible genotype-phenotype correlation. METHODS: 22 unrelated patients with OPMD from Mexico, a previously uncharacterised population, were clinically and molecularly analysed. Detailed ophthalmological and clinical examinations were performed in each proband and molecular analysis of the PABPN1 gene was carried out by PCR amplification and allele-specific cloning/sequencing. Two single nucleotide polymorphisms (SNPs) linked to PABPN1 were determined in each individual and in a number of affected first-degree relatives. RESULTS: 15 subjects (68%) carried a mutant (GCN)(15) or (GCG)(11)(GCA)(3)(GCG) PABPN1 allele; the remaining 7 (32%) exhibited an abnormal (GCN)(13) or (GCG)(9)(GCA)(3)(GCG) allele. Analysis of two SNPs linked to PABPN1 strongly suggests that both expanded alleles originate from two independent founder effects. In addition, in this particular population the (GCN)(15) allele was associated with an earlier onset of the disease (mean 46.5 years) compared with the (GCN)(13) allele (mean 54.7 years). CONCLUSION: The results of this study suggest that OPMD in the Mexican population is mostly due to (GCG)(11) or (GCG)(9) PABPN1 expanded alleles arising from two independent founder effect mutations. These findings add to the definition of the genetic features of the disease and to the establishment of a probable genotype-phenotype correlation.

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 SLC22A12 (URAT1) gene in patients with primary gout.

OBJECTIVE: To analyse the SLC22A12 (URAT1) gene in primary gout patients, first-grade relatives and healthy controls and the possible association of them with demographic and clinical data. SUBJECTS AND METHODS: We included 69 consecutive patients with diagnosis of primary gout, as well as 29 first-grade relatives and 120 healthy volunteers. Demographic and clinical data were obtained from the patients and relatives. DNA was purified from peripheral blood and all 10 exons of the SLC22A12 (URAT1) gene were sequenced. RESULTS: We found six different mutations in the SLC22A12 gene in 16 out of 69 (23%) patients with primary gout. Five mutations were in exon 5 and one in exon 4; five out of six mutations were heterozygous (one compound heterozygous) and one homozygous. The C850G mutation (exon 5) was found in 11 gout patients, these patients have lower levels of triglycerides than the rest of the group: 160 +/- 56 vs 292 +/- 203 mg/dl (P = 0.038). In one family, we found SLC22A12 mutations in three relatives within exon 5. We did not find mutations in the other exons studied (1-3 and 6-10), nor in any of the 10 exons of the 120 healthy volunteers. CONCLUSIONS: We found several mutations in SLC22A12 gene associated with primary gout, the definite role of these mutations in URAT1 activity needs to be further studied.

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.

Tinea imbricata: autosomal dominant pattern of susceptibility in a polygamous indigenous family of the Nahuatl zone in Mexico.

We report on 9 confirmed cases of tinea imbricata (Tokelau, infection due to Trichophyton concentricum) out of 16 family members. They had a common mother with three different fathers. The genetic analysis of the family suggests an autosomal dominant pattern of susceptibility. Most cases (8/9) were presented as concentric and lamellar forms. One patient also had onychomycosis due to T. concentricum. Only two out of nine cases had a positive response to trichophytin.

Unusual clinical presentation in two cases of multiple sulfatase deficiency.

Multiple sulfatase deficiency (MSD) is an inborn error of metabolism that combines the clinical features of late infantile metachromatic leukodystrophy and mucopolysaccharidosis. The characteristic biochemical abnormality is a reduction in the activities of several sulfatases, with consequent tissue accumulation of sulfatides, sulfated glycosaminoglycans, sphingolipids, and steroid sulfates. In this study we present two unusual cases of MSD with variable enzymatic deficiency of arylsulfatases A, B, and C. Both patients had ichthyosis, broad thumbs and index fingers, an unusually slow progression of the neurologic symptoms, and lacked the hepatosplenomegaly that is typical of MSD. Olivopontocerebellar atrophy was present and one patient had a large retrocerebellar cyst. Mucopolysaccharides were not detected in the urine from either subject. Leukocyte arylsulfatase A activity in patient 1 was 0.46 nmol/mg protein/hr and in patient 2 was 0.0 nmol/mg protein/hr (normal 0.7-5.0 nmol/mg protein/hr). Leukocyte arylsulfatase B activity in patient 1 was 24 nmol/mg protein/hr and in patient 2 was 22 nmol/mg protein/hr (normal 115-226 nmol/mg protein/hr). Leukocyte arylsulfatase C in patient 1 was 0.30 pmol/mg protein/hr and in patient 2 was 0.28 pmol/mg protein/hr (normal 0.84 pmol/mg protein/hr). In conclusion, these two patients with MSD had mild clinical presentations not previously reported and variable enzymatic deficiency of arylsulfatases A, B, and C.

Carrier identification by FISH analysis in isolated cases of X-linked ichthyosis.

X-linked ichthyosis (XLI) is an inborn error of metabolism due to steroid sulfatase (STS) deficiency. STS assay and FISH are useful in diagnosing carrier status of XLI. Biochemical analysis appears to indicate that most sporadic cases are inherited. Since this method does not seem to be completely reliable in recognizing XLI-carriers, the aim of the present study was to corroborate by FISH whether or not most sporadic cases of XLI had de novo mutations. XLI patients were classified through STS assay and PCR amplification of 5'-3' ends of the STS gene. XLI patients had undetectable levels of STS activity and complete deletion of the STS gene. Patients' mothers were studied through STS assay and FISH. Nine out of 12 mothers presented an STS activity compatible with XLI-carrier state. These mothers also had only one copy of the STS gene, indicating that they carry the primary gene defect. One mother had normal STS activity but only one copy of the STS gene. This data corroborated that most sporadic cases do not represent de novo mutations, and that FISH must be included in the analysis of mothers of sporadic cases when they present with normal STS activity, in order to correctly diagnose the XLI carrier state.

Deletion of exons 1-5 of the STS gene causing X-linked ichthyosis.

X-linked ichthyosis is an inherited disorder due to steroid sulfatase deficiency. It is clinically characterized by dark, adhesive, and regular scales of the skin. Most X-linked ichthyosis patients present large deletions of the STS gene and flanking markers; a minority show a point mutation or partial deletion of the STS gene. In this study we analyzed the STS gene in a family with simultaneous occurrence of X-linked ichthyosis and ichthyosis vulgaris. X-linked ichthyosis diagnosis was confirmed through steroid sulfatase assay in leukocytes using 7-[3H]-dehydroepiandrosterone sulfate as a substrate. Exons 1, 2, 5, and 6-10, and the 5' flanking markers DXS1130, DXS1139, and DXS996 of the STS gene were analyzed by polymerase chain reaction. X-linked ichthyosis patients of the family (n = 4 males) had undetectable levels of STS activity (0.00 pmol per mg protein per h). The DNA analysis showed that only exons 6-10 and the 5' flanking markers of the STS gene were present. We report the first partial deletion of the STS gene spanning exons 1-5 in X-linked ichthyosis patients.

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.

Mutation report: a novel partial deletion of exons 2-10 of the STS gene in recessive X-linked ichthyosis.

X-linked ichthyosis is an inherited disease due to steroid sulfatase deficiency. Onset is at birth or early after birth with dark, regular, and adherent scales of skin. Approximately 85%-90% of X-linked ichthyosis patients have large deletions of the STS gene and flanking sequences. Three patients have been identified with partial deletions of the gene. Two deletions have been found at the 3' extreme and the other one implicating exons 2-5. This study describes a novel partial deletion of the STS gene in an X-linked ichthyosis patient. The subject was classified through steroid sulfatase assay in leukocytes using 7-[3H]-dehydroepiandrosterone sulfate as a substrate. Exons 1, 2, 5, and 7-10, and 3' flanking sequences DXS1131, DXS1133, DXS237, DXS1132, DXF22S1, and DXS278 of the STS gene were analyzed through polymerase chain reaction. The DNA analysis showed that exon 1 and 3' flanking sequences from DXS237 to DXS278 were present. In this study we report the fourth partial deletion of the STS gene and the first spanning exons 2-10 in X-linked ichthyosis patients.