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Background: The number of APOE-ϵ4 alleles is a major nonmodifiable risk factor for sporadic Alzheimer disease (AD). There is increasing evidence on the benefits of dietary DHA (22:6n-3) before the onset of AD symptoms, particularly in APOE-ϵ4 carriers. Brain alterations in the preclinical stage can be detected by structural MRI. Objectives: We aimed, in middle-aged cognitively unimpaired individuals at increased risk of AD, to cross-sectionally investigate whether dietary DHA intake relates to cognitive performance and to MRI-based markers of cerebral small vessel disease and AD-related neurodegeneration, exploring the effect modification by APOE-ϵ4 status. Methods: In 340 participants of the ALFA (ALzheimer and FAmilies) study, which is enriched for APOE-ϵ4 carriership (n = 122, noncarriers; n = 157, 1 allele; n = 61, 2 alleles), we assessed self-reported DHA intake through an FFQ. We measured cognitive performance by administering episodic memory and executive function tests. We performed high-resolution structural MRI to assess cerebral small vessel disease [white matter hyperintensities (WMHs) and cerebral microbleeds (CMBs)] and AD-related brain atrophy (cortical thickness in an AD signature). We constructed regression models adjusted for potential confounders, exploring the interaction DHA × APOE-ϵ4. Results: We observed no significant associations between DHA and cognitive performance or WMH burden. We observed a nonsignificant inverse association between DHA and prevalence of lobar CMBs (OR: 0.446; 95% CI: 0.195, 1.018; P = 0.055). DHA was found to be significantly related to greater cortical thickness in the AD signature in homozygotes but not in nonhomozygotes (P-interaction = 0.045). The association strengthened when analyzing homozygotes and nonhomozygotes matched for risk factors. Conclusions: In cognitively unimpaired APOE-ϵ4 homozygotes, dietary DHA intake related to structural patterns that may result in greater resilience to AD pathology. This is consistent with the current hypothesis that those subjects at highest risk would obtain the largest benefits from DHA supplementation in the preclinical stage. This trial was registered at clinicaltrials.gov as NCT01835717. © 2021 The Author(s). Published by Oxford University Press on behalf of the American Society for Nutrition.

IntroductionNeuroToolkit is a set of cerebrospinal fluid (CSF) biomarkers developed to identify Alzheimer’s disease co-pathologies, identify and characterize disease progression and treatment response. We assess the association between NeuroToolkit biomarkers and cerebral amyloid deposition in the ALFA+ cohort [1].Methods326 cognitively unimpaired individuals from the ALFA+ cohort [1] underwent a lumbar puncture and amyloid [18F]flutemetamol PET imaging. Biomarkers in NeuroToolkit (Figure 1) were determined using prototype Roche Elecsys® assays. CSF pTau levels were measured using the Elecsys® CSF assay. We cal- culated cross-correlation values between NeuroToolkit biomarkers and Centiloids. Voxel-wise associations between NeuroToolkit biomarkers and [18F]flutemetamol images were sought, accounting for the effect of various demographics. Additional analyses were performed after correcting also for the Aα42/40 ratio or Centiloid values.ResultsFigure 1. Shows associations between NeuroToolkit biomarkers and Centiloids. NeuroToolkit bio- markers were significantly associated with cerebral amyloid deposition measured by [18F]flutemetamol PET (Figure 2). Correcting for global amyloid deposition, higher levels CSF YKL-40, an astroglial activity marker, were associated to increased cerebral amyloid deposition in the inferior and lateral temporal lobe, in parietal and orbitofrontal areas, and the caudate heads (Figure 3).ConclusionsResults of NeuroToolkit biomarkers support early involvement of the astroglial response to cerebral amyloid deposition.DisclosureThis study was conducted through a collaboration with Roche Diagnostics International. These data will be presented at Advances in Alzheimer’s and Parkinson’s Therapies. Ref: Molinuevo. TRCI 2 (2016) 82–92gwendlyn.kollmorgen@roche.com

Aim To compare diagnostic accuracy of Ventilation/Perfusion (V/P) single-photon emission computed tomography (SPECT) combined with simultaneous full-dose CT with a hybrid SPECT/CT scanner versus planar ventilation/perfusion (V/P) SPECT and CT angiography (CTA) in patients suspected with acute pulmonary embolism (PE). Methods Between 2009 and 2011, consecutive patients suspected of acute PE were referred for V/P SPECT/CT (reviewed board approved study). A contrast agent was administered to patients who had no contraindications. Non-contrast V/P SPECT/CT was performed on the remaining patients. All patients were followed-up for at least 3 months. Results A total of 314 patients were available during the study period, with the diagnosis of PE confirmed in 70 (22.29%) of them. The overall population sensitivity and specificity was 90.91% and 92.44%, respectively for V/P SPECT, 80% and 99.15%, respectively, for CTA, and 95.52% and 97.08% for V/P SPECT/CT. SPECT/CT performed better than V/P SPECT (AUC differences = 0.0419, P = 0.0043, 95% CI; 0.0131–0.0706) and CTA (AUC differences = 0.0681, P = 0.0208, 95% CI; 0.0103–0.1259)). Comparing imaging modalities when contrast agent could be administered, sensitivity and specificity increased and V/P SPECT/CT was significantly better than CTA (AUC differences = 0.0681, P = 0.0208, 95% CI; 0.0103–0.1259) and V/P SPECT (AUC differences = 0.0659, P = 0.0052, 95% CI; 0.0197–0.1121). In case of non-contrast enhancement, there was non-significant increase of specificity. Secondary findings on CT impacted patient management in 14.65% of cases. Conclusion Our study shows that combined V/P SPECT/CT scanning has a higher diagnostic accuracy for detecting acute PE than V/P SPECT and CTA alone. When feasible, V/P SPECT/CT with contrast enhancement is the best option.

Resumen Objetivo valorar los resultados de la biopsia del ganglio centinela (BGC) en pacientes con cancer de mama multifocal (CMMF) en comparacion con el unifocal (CMUF). Pacientes y metodos se han realizado e incluido en una base de datos de manera prospectiva 1.535 BGC a pacientes de 9 centros hospitalarios. De ellos 174 presentaban CMMF. Para la BGC se utilizaron coloides de Tc-99 m y la via de administracion fue mayoritariamente la profunda, repartiendo el trazador en los diferentes focos. Resultados el indice de deteccion global fue del 93,8%, sin encontrar diferencias entre ambos grupos (el 94,8% en CMMF frente al 93,4%). La media de GC detectados fue de 1,46, siendo mayor en el grupo CMMF (1,58 frente a 1,45; p=0,036). La localizacion fue extraaxilar en el 19,6%, mas frecuente en el grupo CMMF (el 23,4 frente al 18,9%, no significativo) y mas en el territorio de la cadena mamaria interna y en el nivel III axilar. La incidencia de metastasis en los GC biopsiados fue del 27,3%, mayor en el grupo CMMF (el 29,1 frente al 26,7%, no significativo), con una media de GC afectados mayor (0,42 frente a 0,32, no significativo). En la linfadenectomia axilar se identifico afectacion de ganglios adicionales en una proporcion igual en ambos grupos (29,7%). Conclusiones la BGC parece tener un rendimiento similar en tumores unifocales y multifocales. En tumores multifocales, parece haber un patron de drenaje linfatico especifico, con mayor numero de GC detectados y probablemente con mayor numero de localizaciones de GC extraaxilares.

Purpose: Routine protocols for the study of mental retardation include karyotype, analysis for fragile X syndrome, and subtelomeric rearrangements. Nevertheless, detection of cryptic rearrangements requires more sensitive techniques. Mutation screening in all known genes responsible for X-linked mental retardation is not feasible, and linkage analysis is sometimes limited. Multiplex ligation probe amplification is a recently developed technique based on the amplification of specific probes that allows relative quantification of 40 to 46 different target DNA sequences in a single reaction. Methods: In the present study, we assessed multiplex ligation probe amplification for the detection of microduplications/microdeletions in 80 male patients with suspicion of X-linked mental retardation. Results: We detected four copy number aberrations (5%): three duplications (GDI1, RPS6KA3, and ARHGEF6) and one deletion (OPHN1). All these changes were confirmed by other molecular techniques, and patients were clinically re-evaluated. Conclusions: We strongly recommend the use of multiplex ligation probe amplification as a first screening method for the detection of copy number aberrations in patients with mental retardation because of its cost-effectiveness.

Resumen Objetivo Valorar el rendimiento diagnostico y la eficacia en la deteccion del tejido suprarrenal normofuncionante de la gammagrafia cortical suprarrenal en el hiperaldosteronismo primario, siguiendo el protocolo que combina en un solo estudio la obtencion de imagenes de frenacion e imagenes tardias tras la supresion de la frenacion con dexametasona. Material y metodos Se estudiaron 20 pacientes remitidos a nuestro servicio con la sospecha de hiperaldosteronismo primario y se exploraron mediante gammagrafia combinada. 13 hombres y 7 mujeres, rango de edad de 31 a 73 anos y edad media de 52 anos. Se bloqueo la glandula tiroidea con Lugol y se administro al paciente dexametasona 1 mg c./6h desde 7 dias antes de la dosis hasta el tercer dia de la exploracion, momento en el que se suspendio la frenacion. El radiotrazador fue I-131-norcolesterol (37 MBq e.v.). Adquisicion Estudio planar posterior de 30 min. Detecciones a las 24 y/o 48h y al tercer dia, despues de la cual se suspendio la dexametasona y se obtuvo una ultima deteccion al 5. ° y/o 7. ° dia. El resultado de la gammagrafia se confirmo con la valoracion clinica final (VCF) del paciente. Resultados 11 resultados positivos, 9 catalogados de adenoma hiperfuncionante (8 VP y 1 FP) y dos de hiperplasia bilateral (2VP); 7 fueron negativos (6 VN y 1 VCF no concluyente) y dos gammagrafias indeterminadas (1 incidentaloma y 1 VCF no concluyente). En todos los casos la gammagrafia del 5. ° y/o 7. ° dia mostro la aparicion de las glandulas suprarrenales normofuncionantes. Conclusiones El estudio del funcionalismo suprarrenal mediante el protocolo combinado de gammagrafia suprarrenal con frenacion y suspension de la frenacion con dexametasona permitio identificar con elevada precision diagnostica los hiperaldosteronismos primarios y caracterizar la funcion de las glandulas suprarrenales normales.

Resumen Objetivo Valorar la necesidad de incluir el estudio del gen FMR1 y/o FMR2, dos genes responsables de retraso mental, en los protocolos de estudio de las mujeres que presentan fallo ovarico prematuro (FOP) de causa idiopatica Sujetos y metodos Se ha estudiado la zona repetitiva CGG de los genes FMR1 y FMR2 a 45 mujeres que consultaban al Servicio de Ginecologia o Genetica del Hospital Clinic de Barcelona por presentar menopausia precoz Resultados En 2 mujeres (4,4%) se ha detectado una expansion del triplete CGG en el gen FMR1 correspondiente a una premutacion. No se ha detectado ninguna variacion del rango de la normalidad en el triplete CGG en el gen FMR2. La incidencia de mujeres portadoras de premutacion en el gen FMR1 entre la poblacion de mujeres que presentan menopausia precoz es 11 veces mayor que la de la poblacion general (1/246) Conclusiones Un tercio de los casos de FOP son familiares, lo cual indica la necesidad de los estudios geneticos. Dada la elevada incidencia de portadoras de premutacion en el gen FMR1 en la poblacion de mujeres con FOP, el riesgo que esto comporta para su descendencia (un 50% de riesgo de tener un hijo con retraso mental) y la facilidad del estudio molecular, se recomienda incluir el estudio del gen FMR1 en los protocolos geneticos de FOP

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with FMR1 gene premutation alleles (55-200 CGG repeats). Fragile X-associated tremor/ataxia syndrome clinical core features include action tremor, gait ataxia, cognitive deficits progressing to dementia, and frequently parkinsonism. Although the pathogenic molecular mechanism of FXTAS is not completely understood, the restriction of the phenotype to the FMR1 premutation range has given rise to a model based on a RNA toxic gain-of-function. Since the identification of the first microRNAs (miRNAs) and their role in normal development, several studies have associated them with neurodegenerative diseases such as Parkinson, Alzheimer and Huntington diseases, suggesting that they play a key role in brain development, as well as in its morphogenesis. Herein, we present the characterization of miRNA expression profiles in FXTAS male patients using deep sequencing-based technologies and microarray technology. Deep sequencing analysis evidenced 83 miRNAs that were significantly deregulated whereas microarray analysis showed 31. When comparing these results, 14 miRNAs were found deregulated in FXTAS patients. MiR-424 and miR-574-3p showed significant fold change adjusted P-values in both platforms in FXTAS patients. MiR-424 has been founded substantially and specifically enriched in human cerebral cortical white matter of Alzheimer disease patients, which, together with cerebral atrophy, is a prominent imaging finding in individuals with FXTAS. The study provides the first systematic evidence of differential miRNA expression changes in FXTAS blood samples. Although further studies are necessary to better characterize the miRNA function in FXTAS disorder, our results suggest that they might contribute to its pathogenesis.

Summary Background Familial melanoma, a cluster of several cases within a single family, accounts for approximately 10% of cases of melanoma. Hereditary melanoma is defined as two or more first-degree relatives having melanoma. A member of a melanoma-prone family has a 35–70-fold increased relative risk of developing a melanoma. Genetic susceptibility is linked to the major susceptibility genes CDKN2A and CDK4, and the minor susceptibility gene MC1R. Objectives To determine the clinical and genetic characteristics of cutaneous melanoma in melanoma-prone families from Uruguay. Methods We studied 13 individuals from six melanoma-prone families living in Uruguay. Phenotype, familial and personal history were recorded. Molecular screening of CDKN2A and CDK4 was done by polymerase chain reaction–single strand conformational polymorphism analysis. The MC1R gene was sequenced. Results Mutations in CDKN2A were detected in five of six families: c.−34G>T, p.G101W and p.E88X. A novel germline mutation p.E88X, associated with hereditary melanoma in two unrelated families, is described. We hypothesize that a founder effect occurred probably in the Mediterranean region. No mutations in CDK4 were detected. Six different MC1R variants, all previously reported, were present in Uruguayan families. Conclusions The overall rate of deleterious CDKN2A mutations in our familial melanoma pedigrees, even though the sample size is small, was considerably higher (83%) than the often quoted range.

To evaluate the results for sentinel node biopsy (SNB) in patients with multifocal breast cancer (MBC) in comparison to in those with unifocal breast cancer (UBC).A total of 1535 prospective SNB (174 on patients with MBC) were performed at 9 hospitals. In most patients, Tc-99m albumin colloids were injected intraparenchymally into each tumoral focus for SNB.The overall identification rate was 93.8%; no differences between groups were observed (94.8% in MBC vs 93.4% in UBC). The mean number of sentinel nodes detected was 1.46, being higher in the MBC group than in the UBC group (1.58 vs 1.45; p=0.036). Extra-axillary sentinel nodes were found in 19.6%; extra-axillary sentinel nodes were more common in the MBC group (23.4% vs 18.9%, ns) and in the internal mammary chain and in level III axillary lymph nodes. The incidence of sentinel node metastasis was 27.3% (29.1% MBC vs 26.7% UBC, ns), and the mean number of positive sentinel nodes was 0.42 in the MBC group vs 0.32 in the UBC group (p=ns). Axillary dissection identified the same rate of positive additional nodes (29.7%) in both groups.The diagnostic yield of SNB seems similar in MBC and UBC. In MBC, there appears to be a specific pattern of lymphatic drainage, with a higher number of sentinel nodes detected and probably a higher number of extra-axillary sentinel nodes.

To evaluate the diagnostic performance and efficacy of adrenal scintigraphy in primary aldosteronism following the protocol that combines adrenal suppression scintigraphy plus non-suppression study.20 patients referred to our service with the suspicion of primary aldosteronism were studied by combined scintigraphy. Thirteen men and 7 women, mean age of 52 years, aged from 31 to 73 years, were included. Uptake of free iodine by the thyroid was inhibited by oral Lugol 5 % administration. Dexamethasone 4 mg per day was administered from day 7 to the third day of detection, when administration was stopped. Adrenal scintigraphy was performed after intravenous injection of I-131-norcolesterol (37 MBq). Images were taken at 24 and/or 48 hours and on the third day. Afterwards, dexamethasone administration was stopped and late images on 5th and/or 7th days were obtained. The scintigraphic result was confirmed with the final clinical evaluation (FCE) of the patient.11 patients presented pathological studies, 9 adenomas (8TP + 1FP) and 2 bilateral adrenal hyperplasia (2TP); 7 normal scintigraphies (6TN and 1 non-conclusive FCE) and 2 non-conclusive scintigraphies (1 incidentaloma and 1 non-conclusive FCE). Normal adrenal glands were visualized in all cases on the 5th and/or 7th day scintigraphy.The study of adrenal functionalism by the combined protocol of adrenal suppression study plus later non-suppression study made it possible to identify with high precision primary aldosteronism and to confirm the function of normal adrenal glands.

Mental retardation affects 1-3% of the general population, and the genetic causes in many cases are unknown. Cytogenetically undetected chromosomal imbalances have been indicated as an explanation. Nowadays, due to the development of molecular cytogenetic techniques, it is possible to identify cryptic rearrangements involving the ends of chromosomes. We report a screening using chromosome-specific telomere fluorescence in-situ hybridization (FISH) probes, in a group of 30 patients with a well-characterized phenotype including mental retardation, dysmorphic features, and a normal karyotype. Among them, two subtelomeric rearrangements have been detected and characterized. One of them is a de novo deletion of 1p36, which has been previously described as a new contiguous gene syndrome. The second is an unbalanced product of a cryptic translocation involving chromosomes 1 and 13, which results in a partial 1q trisomy and partial 13q monosomy. These findings highlight, the importance of searching for cryptic subtelomeric rearrangements in non-syndromic mentally retarded patients.

Fragile X syndrome (FXS) is the most common form of inherited mental retardation. Clinical manifestations are due to the absence of the FMRP protein. Affected patients have widely variable phenotypes which are more variable in females than males, presumable due to X inactivation. We report the expression pattern of FMRP in cerebral cortex and ovary in a control and a full-mutated female fetus. FMRP was expressed in mutated and control fetal tissues, although at different levels and patterns. Control fetal cerebral cortex showed FMRP expression in almost all cells, whereas the full mutation carrier showed FMRP positivity in roughly 50% of cortical cells without any specific pattern. In the ovary samples, FMRP expression was seen in all germ cells surrounded by FMRP-negative paragranulosa and interstitial cells. The Müllerian epithelium of the fetal Fallopian tube was continuously positive in the control case, whereas the full mutation carrier showed a discontinuous patchy pattern. Expression of homologue proteins FXR1P and FXR2P showed no differences between control and full mutation fetuses. The pattern of FMRP expression in full mutation carrier females is in agreement with a random X-inactivation in maturing fetal tissues. Immunohistochemical results on cerebral tissues provide a clue for the variation of mental affection among female carriers, depending not only on the number of cells devoid of FMRP, but also on the ultimate destination of those cells in sensitive or more silent location for a proper cerebral development.

Fragile X syndrome is the most common inherited form of mental retardation. The absence of FMRP protein, codified by the FMR1 gene, results in fragile X phenotype. DNA-based diagnostic methods determine the length of the CGG repeat within the FMR1 gene, the main mutation causing the syndrome. Immunohistochemical diagnostic tests detect all mutations leading to the absence of FMRP expression. Results of the antibody test on hair roots correlate with intellectual quotient in affected men and women.Immunohistochemical techniques were used to study FMRP expression in hair roots in a control group to establish the correlation with the length of the CGG repeat. Subsequently, 65 girls and boys with mental retardation attending special schools were screened by using the FMRP test on hair roots.Males and females molecularly characterized as within the normal and premutated range expressed FMRP in more than 70 % of hair roots. Full mutation carriers expressed FMRP in less than 70 % of hair roots. Immunohistochemical studies in males and females with mental retardation led to the identification of one affected male.Fragile X syndrome detection by immunohistochemical testing of hair roots is a valid method of population screening because of the relative noninvasiveness of obtaining samples, and the ease and rapidness of the technique, which can be applied to routine clinical practice.

Although it is generally accepted that women who are carriers of the premutation of the fragile X syndrome (FXS) show no pathological clinical features, several studies have shown that they have a higher incidence of premature failure of their ovaries (early menopause) than the general population. However, when women who are carriers of the complete mutation are studied, no relation is seen between the two conditions. All women who are carriers of the premutation of the FMR1 gene should be informed that they have a greater possibility than the general population (10-15 times) of having an early menopause. Pre-implantation genetic diagnosis (PGD) is a technique used in diagnosis, based on genetic analysis of an embryo obtained by in vitro fertilization (IVF) and subsequently transferred to genetically healthy viable embryos. Preconception genetic diagnosis is based on the genetic study of an ovule before fertilization and subsequent IVF of healthy ovules. The methodology is similar in both cases. Genetic study of FXS is especially difficult because of the large number of CGG repetitions in affected. Often indirect diagnosis has to be made. Both diagnoses have a series of evident advantages over prenatal diagnosis. There is no pregnancy present so the stress and emotional trauma of VIP (voluntary interruption of pregnancy) is avoided. However, it should be pointed out that there are technical drawbacks regarding genetic analysis and the need to resort to IVF in fertile couples.

Controversial data have been reported about SCA8 since its description in 1999. The most accepted hypothesis is that CTG expansions within the CTA/CTG combined repeat expansion in the SCA8 locus causes SCA8. It is inherited as a dominant trait with reduced penetrance. The present study, reports the first data regarding SCA8 in the Spanish population and the clinical findings in patients carrying expanded alleles, including one homozygous patient. Two hundred and forty-six individuals from the Spanish population, including controls (149) and ataxic patients (97), were studied. DNA was extracted from blood samples using standard methods. Amplification of the CTA/CTG 3'untranslated region was achieved by PCR using primers SCA8-F3 and SCA8-R4 and conditions described previously. Neurological reevaluation was done in individuals carrying the expanded allele. We detected five unrelated expanded alleles corresponding to three affected patients (one of them homozygous) and one healthy individual. SCA8 represents 4% of the total dominant spinocerebellar ataxias studied in our group (Spanish population) (three index patients out of 75 dominant ataxic independent nucleus). The patient that resulted homozygous for the expansion is a 25-year-old man with a clinical picture of progressive ataxia and dysarthria that began at the age of 12. On neurological examination, he showed ataxia, slight dysarthria and nystagmus to the extreme lateral gaze. A cranial MRI showed global atrophy of cerebellum but the brainstem was spared. Family history showed the presence of ataxia in his grandfather and father. His mother is healthy at the age of 52 and a molecular study of SCA8 reveals one allele that could be considered as premutated. She has no ataxia antecedents in her family. Our results provide additional information about the SCA8 expansion, within the Spanish population. These results are in agreement with the hypothesis of the CTG expansion in the SCA8 locus being responsible for the SCA8 ataxia showing reduced penetrance. Besides homozygous status, advancing age at onset (as previously described for other SCAs) supports this idea.

PKU is an autosomal recessive disorder. There is a broad spectrum phenotype which depends mainly on residual enzymatic activity and also on other factors such as modifying genes and non-genetic factors. This fact makes us consider that a multidisciplinary study of these patients is necessary to improve knowledge of the condition.To establish phenotype-genotype correlation and classify nine new mutations according to severity.We evaluated the clinical data obtained from a multidisciplinary trial of 11 patients with PKU/HPA who presented with nine new mutations (P275S, P279fsdelC, V388delTG, N61/I62/T63fsdel5bp, P281S, P362T, H1OOR, I164V and Y168H) identified during a molecular study of the PAH gene done in Catalonia (Spain).In our patients the genotype is correlated with the biochemical phenotype whereas the cognitive phenotype depends on determining factors such as early diagnosis and diet. Therefore, although PKU may be considered to be a complex characteristic, the mutations in the PAH gene are the main determining factor of the metabolic phenotype of PKU. A multidisciplinary study is the best way to understand and control these patients.

The fragile X syndrome is due to an expansion of the CGG trinucleotide repeat in the FMR1 gene and hypermethylation of its 5' upstream CpG island in about 95% of the cases. The remaining 5% of cases correspond to other molecular alterations in FMR1 gene such as partial or complete deletions, or point mutations within the coding sequence. We selected 31 patients with clinical manifestations of fragile X syndrome, scoring 16 or more in Hagerman's checklist, but without the CGG expansion. We performed single-strand conformation polymorphism analysis using a nonradioactive technique (silver staining) and we detected six anomalous migrations that, by sequence analysis, corresponded to six nucleotide changes. We screened two different populations (control and fragile X) for these changes, and concluded that they correspond to five new polymorphisms within the FMR1 gene and to one possible synonymous mutation.

PKU is one of the commonest genetic disease in man, affecting 1/10,000 individuals. It presents a wide phenotypical spectrum, from classic PKU to moderate Hyperpheylalaninemia depending on the residual enzymatic activity. Two novel mutations 1163/1164delTG and P362T in exon 11 have been detected during the mutational screening of the PAH gene in 84 families. 1163/1164delTC can be confused with V388M if the mutational screening is performed with BsaAI restriction enzyme, this mutation in heterozigosis presents a moderate phenotype. P362T mutation in heterozigosis with V388M shows a classical PKU phenotype. We report here two new mutations in exon 11 of the PAH gene (GenBank U49897), V1163delTG and P362T (using cDNA sequence), detected during the analysis of 57 PKU and 36 HPA patients belonging to 84 unrelated families detected under a neonatal screening program performed in Catalonia.

Introduccion. El retraso mental (RM) es la discapacidad mas frecuente y con mayor impacto en la vida de la persona afectada, su familia y la sociedad, con una incidencia estimada de un 1-3% en las poblaciones desarrolladas. Entre las causas que lo originan, un 30% parece ser de origen genetico, un 15% de origen ambiental, y el resto se desconoce. Objetivo. Dar una vision actualizada de las causas geneticas del RM y de como las recientes metodologias permiten alcanzar un diagnostico cada dia en un numero mayor de casos para llegar a la prevencion mediante el consejo genetico. Desarrollo. Las causas del RM son extremadamente heterogeneas. Las causas geneticas podemos agruparlas en: alteraciones cromosomicas (aneuploidias, reordenamientos subtelomericos, sindromes microdelecionales o microduplicacionales), alteraciones monogenicas, metabolicas y multifactoriales. Gracias al desarrollo de nuevas tecnicas de alta resolucion -arrays de hibridacion genomica comparada (CGH) y multiplex ligation probe amplification (MLPA)- se pueden detectar microduplicaciones y microdeleciones a lo largo de todo genoma, lo que esta contribuyendo a la identificacion de nuevos sindromes y genes asociados al RM. Conclusiones. Las bases geneticas del RM son muy variadas y complejas. Actualmente disponemos de tecnologia para realizar muchos tipos de estudios; no obstante, casi la mitad de los casos de RM quedan sin diagnosticar. Los antecedentes familiares, si son positivos, permitiran emitir un consejo genetico aunque no tengamos un diagnostico. Es necesario llegar a un diagnostico exacto para poder ofrecer un diagnostico prenatal o preimplantacional.

Introduccion. El estudio del retraso mental (RM) es uno de los campos mas complejos en genetica humana, debido a que presenta una heterogeneidad clinica y genetica muy elevada, con una gran complejidad de las bases geneticas y ambientales que influyen sobre estas. En estos momentos, casi la mitad de los RM quedan sin un diagnostico. Objetivo. Presentar un protocolo de actuacion en el laboratorio mediante la tecnologia de que disponemos actualmente para llegar al diagnostico del RM. Desarrollo. El primer paso es la evaluacion del paciente con una exploracion clinica minuciosa y la obtencion de datos sobre antecedentes personales y familiares. Ante una sospecha diagnostica de uno o varios sindromes que cursan con RM, esta debera confirmarse en el laboratorio, si es posible, con la tecnica correspondiente. Ante casos de RM en los que no existe sospecha clinica para ningun sindrome determinado se realizaran tres pruebas: cariotipo, estudio molecular de la expansion CGG del gen FMR1 y estudio de las regiones subtelomericas. Si el estudio es negativo y se trata de un caso familiar con una estructura adecuada, realizaremos un estudio de ligamiento. En cuanto a los casos esporadicos es dificil avanzar de forma rutinaria, aunque hay algunas pruebas que permiten realizar determinaciones de varios genes a la vez. Existen otras tecnicas encaminadas a profundizar mas, como los cribados de genes responsables de RM inespecifico ligado al cromosoma X o los arrays-CGH (arrays basados en la hibridacion genomica comparada) para todo el genoma o para un cromosoma determinado, pero por el momento estan limitados a proyectos de investigacion o a casos muy concretos. Conclusiones. Proponemos un protocolo de estudio y destacamos la importancia de su utilizacion con el fin de obtener el maximo rendimiento para lograr un diagnostico que nos permita dar el consejo genetico y ofrecer un diagnostico prenatal par futuras generaciones.