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Glycogen Storage Disease type III (GSD III) is an autosomal recessive disorder in which a mutation in the AGL gene causes deficiency of the glycogen debranching enzyme. In childhood, it is characterized by hepatomegaly, keto-hypoglycemic episodes after short periods of fasting, and hyperlipidemia. In adulthood, myopathy, cardiomyopathy, and liver cirrhosis are the main complications. To determine the genotype of the GSD III patients (n = 14) diagnosed and treated in our center, mutation analysis was performed by either denaturing gradient gel electrophoresis or full gene sequencing. We developed, validated and applied both methods, and in all patients a mutation was identified on both alleles. Five novel pathogenic mutations were identified in seven patients, including four missense mutations (c.643G>A, p.Asp215Asn; c.655A>G, p.Asn219Asp; c.1027C>T, p.Arg343Trp; c.1877A>G, p.His626Arg) and one frameshift mutation (c.3911delA, p.Asn1304fs). The c.643G>A, p.Asp215Asn mutation is related with type IIIa, as this mutation was found homozygously in two type IIIa patients. In addition to five novel mutations, we present new genotype-phenotype relationships for c.2039G>A, p.Trp680X; c.753_756delCAGA, p.Asp251fs; and the intron 32 c.4260-12A>G splice site mutation. The p.Trp680X mutation was found homozygously in four patients, presenting a mild IIIa phenotype with mild skeletal myopathy, elevated CK values, and no cardiomyopathy. The p.Asp251fs mutation was found homozygously in one patient presenting with a severe IIIa phenotype, with skeletal myopathy, and severe symptomatic cardiomyopathy. The c.4260-12A>G mutation was found heterozygously, together with the p.Arg343Trp mutation in a severe IIIb patient who developed liver cirrhosis and hepatocellular carcinoma, necessitating an orthotopic liver transplantation.

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The Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV; Wechsler, 2008 ) no longer provides the "traditional" Verbal IQ and Performance IQ deviation scores. In the current study, we investigated the structural validity of these scores in the scale's predecessor, the WAIS-Third Edition (WAIS-III; Wechsler, 1997c ), which is still widely used in clinical practice, especially outside the United States. Confirmative (CFA) and exploratory factor analyses (EFA) were performed on WAIS-III data from a Dutch sample of 247 psychiatric patients. Four competing models were tested in the CFA on 11 subtests. The model that fit the data best was a model in which subtests loaded on the four factor indexes (i.e., 3 Verbal Comprehension subtests, 3 Perceptual Organization subtests, 3 Working Memory subtests, and 2 Processing Speed subtests) as proposed by the manual (Wechsler, 1997b ). In the EFA on 13 subtests with four factors extracted, all subtests were found to load on the factors in accordance with the WAIS-III test manual. However, Picture Arrangement, Arithmetic, and Picture Completion showed only moderate loadings on the proposed factors. Implications for clinical practice are discussed.

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There are indications that the interpersonal affective factor and the social deviation factor, both of which are underlying dimensions of psychopathy, have a positive and a negative relationship, respectively, with executive functioning. However, this is seldom taken into consideration in the research on the relationship between executive functioning and psychopathy, which may be an explanation for the many inconsistent results in this area as reported in the literature (e.g., Rogers, 2006). In the present study, executive functioning was studied using the Wisconsin Card Sorting Test (WCST) in 53 inpatients of a Dutch forensic psychiatric clinic who were classified by means of the Psychopathy Checklist-Revised (PCL-R). Special attention was given to the relationship between the two separate factors and executive functioning. Age, educational level, and substance abuse were controlled for in the analysis. No difference was found between psychopathic (N=17) and nonpsychopathic (N=36) patients in the WCST scoring categories, nor was there a significant difference in the four diagnostic subgroups defined by the two factors. However, the trends observed do justify further study in this direction.

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Colorectal cancer (CC) is the secondary cause of death in the Western countries of which approximately 15% are considered to be hereditary. The hereditary forms are Familial Adenomatous Polyposis (FAP) and Hereditary Non Polyposis Colorectal Cancer (HNPCC) which is the commonest form. The detection of mutations in the MMR and apc related genes, allows the development of health prevention strategies. Different molecular diagnostic strategies are available for the detection of mutations in these genes, i.e. DGGE, SSCP and direct sequencing. However, deletions and duplications of one or more consecutive exons, which account for around 50% of the total alterations in MMR genes, cannot be detected by PCR based methodologies due to the non quantitative nature of these techniques. The aim of our work has been the standardization of a methodology, called Multiplex Ligation-Dependent Probe Amplification, which allows the detection of genomic deletions and duplications as primary analysis in HNPCC and FAP patients in Argentina. In this case, we inform that the application of MLPA allowed the detection of a missence mutation, without the need for direct sequencing of the complete genes involved. A PCR/RFLP strategy was afterwards designed to detect the C

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Hypohidrotic ectodermal dysplasia (HED) can be caused by mutations in the X-linked ectodysplasin A (ED1) gene or the autosomal ectodysplasin A-receptor (EDAR) and EDAR-associated death domain (EDARADD) genes. X-linked and autosomal forms are sometimes clinically indistinguishable. For genetic counseling in families, it is therefore important to know the gene involved. In 24 of 42 unrelated patients with features of HED, we found a mutation in ED1. ED1-negative patients were screened for mutations in EDAR and EDARADD. We found mutations in EDAR in 5 of these 18 patients. One mutation, p.Glu354X, is novel. In EDARADD, a novel variant p.Ser93Phe, probably a neutral polymorphism, was also found. Clinically, there was a difference between autosomal dominant and autosomal recessive HED patients. The phenotype in patients with mutations in both EDAR alleles was comparable to males with X-linked HED. Patients with autosomal dominant HED had features comparable to those of female carriers of X-linked HED. The teeth of these patients were quite severely affected. Hypohidrosis and sparse hair were also evident, but less severe. This study confirms Chassaing et al's earlier finding that mutations in EDAR account for approximately 25% of non-ED1-related HED. Mutations leading to a premature stop codon have a recessive effect except when the stop codon is in the last exon. Heterozygous missense mutations in the functional domains of the gene may have a dominant-negative effect with much variation in expression. Patients with homozygous or compound heterozygous mutations in the EDAR gene have a more severe phenotype than those with a heterozygous missense, nonsense or frame-shift mutation.

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Lynch syndrome (HNPCC) is a dominantly inherited disorder characterized by germline defects in DNA mismatch repair (MMR) genes and the development of a variety of cancers, predominantly colorectal and endometrial. We present a 44-year-old woman who was shown to carry the truncating MSH2 gene mutation that had previously been identified in her family. Recently, she had been diagnosed with an undifferentiated carcinoma of the thyroid and an adenoma of her coecum. Although the thyroid carcinoma was not MSI-high (1 out of 5 microsatellites instable), it did show complete loss of immunohistochemical expression for the MSH2 protein, suggesting that this tumour was not coincidental. Although the risks for some tumour types, including breast cancer, soft tissue sarcoma and prostate cancer, are not significantly increased in Lynch syndrome, MMR deficiency in the presence of a corresponding germline defect has been demonstrated in incidental cases of a growing range of tumour types, which is reviewed in this paper. Interestingly, the MSH2-associated tumour spectrum appears to be wider than that of MLH1 and generally the risk for most extra-colonic cancers appears to be higher for MSH2 than for MLH1 mutation carriers. Together with a previously reported case, our findings show that anaplastic thyroid carcinoma can develop in the setting of Lynch syndrome. Uncommon Lynch syndrome-associated tumour types might be useful in the genetic analysis of a Lynch syndrome suspected family if samples from typical Lynch syndrome tumours are unavailable.

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Hereditary non-polyposis colorectal carcinoma (HNPCC) is an autosomal dominant disorder associated with colorectal and endometrial cancer and a range of other tumor types. Germline mutations in the DNA mismatch repair (MMR) genes, particularly MLH1, MSH2, and MSH6, underlie this disorder. The vast majority of these HNPCC-associated mutations have been proven, or assumed, given the family history of cancer, to be transmitted through several generations. To the best of our knowledge, only a single case of a de novo germline MMR gene mutation (in MSH2) has been reported till now. Here, we report a patient with a de novo mutation in MLH1. We identified a MLH1 Q701X truncating mutation in the blood lymphocytes of a male who had been diagnosed with rectal cancer at the age of 35. His family history of cancer was negative for the first- and second-degree relatives. The mutation could not be detected in the patient' parents and sibling and paternity was confirmed with a set of highly polymorphic markers. Non-penetrance and small family size is the common explanation of verified negative family histories of cancer in patients with a germline MMR gene mutation. However, in addition to some cases explained by non-paternity, de novo germline mutations should be considered as a possible explanation as well. As guidelines that stress not to restrict MMR gene mutation testing to patients with a positive family history are more widely introduced, more cases of de novo MMR gene germline mutations may be revealed.

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