Clinical, imaging, and molecular findings in a sample of Mexican families with pantothenate kinase-associated neurodegeneration.

Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive disorder characterized by iron accumulation in the brain, because of mutations in the PANK2 gene. Phenotypic and genotypic characteristics of 11 patients from five Mexican families with PKAN disease are reported. Sequencing of PANK2 confirmed the diagnosis. The 11 patients had dysarthria associated with dystonia and Parkinsonism in six. Brain magnetic resonance imaging (MRI) showed the 'eye-of-the-tiger' sign in all patients. Three different mutations were identified, a novel one (p.A469P) and two (p.G219V and p.N404I) very rare. Homozygous sibs for the p.G219V mutation had a severe disease progression with early death. Dystonia predominated in the p.A469P/p.N404I compound heterozygous patients. Homozygous for p.N404I showed Parkinsonism, tics and personality and speech disorders. Early and late disease onset and variable expression was present in carriers of the different identified mutations. The 'eye-of-the-tiger' is an excellent neuroimaging hallmark to predict PANK2 mutations. We detected a 'cluster' of patients harboring the p.N404I mutation, strongly suggesting a founder effect for this mutation. This is the first familial clinical-genetic PKAN disease study accomplished in Mexico.

A novel gene mutation in PANK2 in a patient with an atypical form of pantothenate kinase-associated neurodegeneration.

Pantothenate kinase-associated neurodegeneration (PKAN) disease is an autosomal recessive neurodegenerative disorder with iron storage in the brain due to PANK2 gene mutations. Brain magnetic resonance imaging (MRI) shows the typical "eye-of-the-tiger" sign. The aim of the present study was to describe clinical, MRI and molecular findings in a 26-year-old male with atypical PKAN disease in whom, brain MRI scans showed bilateral pallidal T2-hypointensity with a small central region of T2-hyperintensity, resembling the "eye-of-the-tiger" typical image. Genetic analysis identified two mutations in PANK2: c.1561G>A and c.1663G>A, being the latter never described before. Due to limited phenotype-genotype correlation among patients with movement disorders, if "eye-of-the-tiger" brain MRI is present, PANK2 mutations investigation are needed to confirm PKAN disease.

[Hyperhomocysteinemia as risk factor in a Mexican population]. / La hiperhomocisteinemia como factor de riesgo en una población mexicana.

Hyperhomocysteinemia is considered one of the emerging risk factors for the development of coronary artery disease (CAD). In order to know the prevalence of this metabolic disorder in a Mexican population with early CAD (< 50 years), we studied a group of these patients and compared the levels of homocysteine with a group of patients, paired by age and gender, without angiographic evidence of coronary atherosclerosis. Preliminary results show that the population with early CAD has more traditional risk factors, specially diabetes mellitus, and higher levels of homocysteine in plasma. Moreover there is a genetic factor with higher incidence of a TT homozygotic mutation of the MTHFR that increases homocysteine because of an altered folate metabolism.

A case of Kearns-Sayre syndrome with the 4,977-bp common deletion associated with a novel 7,704-bp deletion.

Mitochondria from a patient diagnosed with Kearns-Sayre syndrome (KSS) exhibited severely diminished cytochrome c oxidase activity and at least four mitochondrial DNA (mtDNA) species: 9%-11% of the fulllength mtDNA (16.6 kb), 70%-75% of a 11.7-kb population (harboring the 4,977-bp common deletion), 2%-3% of a 10.5-kb population, and 12%-17% of a 8.9-kb population. The 8.9-kb mtDNA exhibited a secondary deletion that extended 7,704 bp from nucleotide 7,979 in the cox2 gene to nucleotide 15,683 in the cytb gene. To our knowledge, this is the first description of the presence of at least two large-scale deletions of mtDNA in KSS.

High prevalence of the thermolabile methylenetetrahydrofolate reductase variant in Mexico: a country with a very high prevalence of neural tube defects.

Neural tube defects (NTD) are highly prevalent in the Mexican population. According to data from the Registry and Epidemiological Surveillance of External Congenital Malformations (RYVEMCE), at least 1 in 250 conceptions that reach 20 weeks of pregnancy or more has a NTD. This number is three to four times higher than that observed in other related ethnic groups. A common novel mutation (C677T) in the methylenetetrahydrofolate reductase (MTHFR) gene is considered an associated risk factor for NTD and other malformations. Studies in different populations agree that the prevalence of the homozygote for the mutated allele is higher in cases of NTD than in controls. In a meta-analysis recently published, the mean prevalence of the homozygote for the mutation was 9.2% for different groups of European controls and 16.4% in NTD cases from the same populations. This prompted us to investigate the frequency of the normal (C) and the mutant (T) alleles and the prevalence of the expected (CC, CT and TT) genotypes in 250 healthy Mexican women from different parts of the country. The proportion of CC (17.6%), CT (47.6%), and TT (34. 8%) genotypes found, and the gene frequencies of 0.414 and 0.586% for the C and T alleles, respectively, confirmed the very high prevalence of the mutant allele and the TT genotype in the sample studied. Comparisons with studies done in Holland, Ireland, the United States, Japan, and other ethnic groups showed highly significant differences, with an average OR of 5.8 (95% Cl 3.4-10.3) for a Mexican being homozygous for the mutation. These findings may explain an important part of the high prevalence of NTD observed in our population.

Miller-Dieker syndrome and trisomy 5p in a child carrying a derivative chromosome with a microdeletion in 17p13.3 telomeric to the LIS1 and the D17S379 loci.

Trisomy 5p and Miller-Dieker syndromes frequently are the result of unbalanced segregations of reciprocal translocations of chromosomes 5 and 17 with other autosomes. The critical regions for the expression of the mentioned syndromes have been mapped to 5p13-->pter, and 17p13.3-->pter. In this report, we describe an 8-year-old girl with mental retardation, postnatal growth deficiency, generalized muscular hypotonia, seizures, microcephaly, cortical atrophy, partial agenesis of corpus callosum, cerebral ventriculomegaly, facial anomalies, patent ductus arteriosus, pectus excavatum, long fingers, and bilateral talipes equinovarus caused by the presence of a 46,XX,der(17)t(5;17)(p13.1;p13.3)mat chromosome complement. Cytogenetic studies of the family confirmed a balanced reciprocal translocation (5;17)(p13.1;p13.3) in her mother, maternal grandfather, maternal aunt, and a female first cousin. Fluorescence in situ hybridization studies on the mother and the proposita using three probes, which map to distal 17p, confirmed the reciprocal translocation in the mother and a terminal deletion in the patient, which resulted in the retention of LIS1 and D17S379 loci and deletion of the 17p telomere. These findings and the phenotype of the proposita, strongly suggest that genes telomeric to LIS1 and locus D17S379 are involved in many clinical findings, including the minor facial anomalies of the Miller-Dieker syndrome.

The spectrum of congenital anomalies of the VATER association: an international study.

The spectrum of the VATER association has been debated ever since its description more than two decades ago. To assess the spectrum of congenital anomalies associated with VATER while minimizing the distortions due to small samples and referral patterns typical of clinical series, we studied infants with VATER association reported to the combined registry of infants with multiple congenital anomalies from 17 birth defects registries worldwide that are part of the International Clearinghouse for Birth Defects Monitoring Systems (ICB-DMS). Among approximately 10 million infants born from 1983 through 1991, the ICB-DMS registered 2,295 infants with 3 or more of 25 unrelated major congenital anomalies of unknown cause. Of these infants, 286 had the VATER association, defined as at least three of the five VATER anomalies (vertebral defects, anal atresia, esophageal atresia, renal defects, and radial-ray limb deficiency), when we expected 219 (P<0.001). Of these 286 infants, 51 had at least four VATER anomalies, and 8 had all five anomalies. We found that preaxial but not other limb anomalies were significantly associated with any combination of the four nonlimb VATER anomalies (P<0.001). Of the 286 infants with VATER association, 214 (74.8%) had additional defects. Genital defects, cardiovascular anomalies, and small intestinal atresias were positively associated with VATER association (P<0.001). Infants with VATER association that included both renal anomalies and anorectal atresia were significantly more likely to have genital defects. Finally, a subset of infants with VATER association also had defects described in other associations, including diaphragmatic defects, oral clefts, bladder exstrophy, omphalocele, and neural tube defects. These results offer evidence for the specificity of the VATER association, suggest the existence of distinct subsets within the association, and raise the question of a common pathway for patterns of VATER and other types of defects in at least a subset of infants with multiple congenital anomalies.

Hormone therapy during pregnancy and isolated hypospadias: an international case-control study.

Mothers of boys with hypospadias and control mothers were interviewed in eight malformation monitoring programs around the world. Hormone therapy was used quite frequently in five but rarely in three of the programs. The odds ratio for hypospadias after hormone therapy during pregnancy was 2.8 (95% confidence limits 1.2, 6.9) but there was no correlation between the timing of hormone therapy and the location of the urethral orifice, nor between the severity of the malformation and hormone therapy. Programs with the highest hormone exposure rate showed the lowest odds ratio for pregnancy bleeding, the most common reason for hormone therapy. These latter findings cast doubts on the causal association between hormone therapy and isolated hypospadias. Alternative explanations are recall or interviewer bias or unidentified confounders.