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Resumen Introduccion La ARCA1/SCAR8 es una heredoataxia recesiva causada por mutaciones en el gen SYNE1, que fue descrita inicialmente en familias francocanadienses (Quebec) con un sindrome cerebeloso puro. En la actualidad se reporta cada vez mas este tipo de ataxia en otras partes del mundo y con un fenotipo muy variable. Recientemente se han notificado casos de distrofia muscular, artrogriposis y miocardiopatia por mutaciones de este gen. Objetivos Describir los hallazgos clinicos y moleculares en 3 familias espanolas de diferente origen geografico, las primeras en las que se confirmo el diagnostico de ARCA1/SCAR8 con analisis molecular. Material y metodos Evaluacion clinica, pruebas paraclinicas y estudio genetico en 4 pacientes (3 varones y una mujer), diagnosticados en distintos servicios de neurologia espanoles. Resultados Los sintomas cerebelosos comenzaron en todos los casos en la tercera-cuarta decadas. Tras 15 anos de evolucion, 3 pacientes presentaban un sindrome cerebeloso puro similar a la descripcion original, mientras que un paciente con mas de 30 anos de evolucion presentaba tambien paralisis de mirada vertical, afectacion piramidal y moderado deterioro cognitivo. El estudio de resonancia magnetica mostro en todos los casos atrofia restringida al cerebelo. La secuenciacion de SYNE1 permitio identificar distintas variantes patogenicas en cada familia. Conclusiones La ARCA1/SCAR8 tiene una distribucion mundial con una gran diversidad de mutaciones en SYNE1. Ademas de ataxia puede dar lugar a un complejo fenotipo de inicio y gravedad muy variable.

Introduction In 2009, we described a possible founder effect of autosomal dominant Segawa disease in Cordoba (Spain) due to mutation c.265C>T (p. Q89*) in the GCH1 gene. We present a retrospective multicentre study aimed at improving our knowledge of Segawa disease in Spain and providing a detailed phenotypic-genotypic description of patients. Methods Clinical-genetic information were obtained from standardized questionnaires that were completed by the neurologists attending children and/or adults from 16 Spanish hospitals. Results Eighty subjects belonging to 24 pedigrees had heterozygous mutations in GCH1. Seven genetic variants have been described only in our cohort of patients, 5 of which are novel mutations. Five families not previously described with p. Q89* were detected in Andalusia due to a possible founder effect. The median latency to diagnosis was 5 years (IQR 0–16). The most frequent signs and/or symptoms were lower limb dystonia (38/56, 67.8%, p = 0.008) and diurnal fluctuations (38/56, 67.8%, p = 0.008). Diurnal fluctuations were not present in the phenotypes other than dystonia. Fifty-three of 56 symptomatic patients were treated with a levodopa/decarboxylase inhibitor for (mean ± SD) 12.4 ± 8.12 years, with 81% at doses lower than 350 mg/day (≤5 mg/kg/d in children). Eleven of 53 (20%) patients had non-responsive symptoms that affected daily life activities. Dyskinesias (4 subjects) were the most prominent adverse effects. Conclusion This study identifies 5 novel mutations and supports the hypothesis of a founder effect of p. Q89* in Andalusia. New insights are provided for the phenotypes and long-term treatment responses, which may improve early recognition and therapeutic management.

Introduction The pathophysiology of PD (Parkinson's disease) has been related to the ubiquitin proteasome system and oxidative stress. Parkin acts as ubiquitin ligase on several substrates. Because genetic variants often have different frequencies across populations, population specific analyses are necessary to complement and validate results from genome-wide association studies. Methods We carried out an association study with genes coding for parkin substrates and cellular stress components in the Galician population (Northern Spain). SNCA and MAPT SNPs were also analyzed. We studied 75 SNPs in a discovery sample of 268 PD patients and 265 controls from Galicia. A replication sample of 271 patients and 260 controls was recruited from Mexico City. Results We observed significant association between PD and SNPs in MAPT. Nominal p-values < 0.05 were obtained in the Galician cohort for SNPs in SYT11, coding for synaptotagmin XI. These results were replicated in the Mexican sample. Discussion The associated markers lie within a ~ 140 kb strong linkage disequilibrium segment that harbors several candidate genes, including SYT11. SNPs from the GBA-SYT11-RAB25 region have been previously associated with PD, however the functionally relevant variants remain unknown. Our data support a likely role of genetic factors within 1q22 in PD susceptibility.

The diagnostic gap for rare neurodegenerative diseases is still considerable, despite continuous advances in gene identification. Many novel Mendelian genes have only been identified in a few families worldwide. Here we report the identification of an autosomal-dominant gene for hereditary spastic paraplegia (HSP) in 10 families that are of diverse geographic origin and whose affected members all carry unique truncating changes in a circumscript region of UBAP1 (ubiquitin-associated protein 1). HSP is a neurodegenerative disease characterized by progressive lower-limb spasticity and weakness, as well as frequent bladder dysfunction. At least 40% of affected persons are currently undiagnosed after exome sequencing. We identified pathological truncating variants in UBAP1 in affected persons from Iran, USA, Germany, Canada, Spain, and Bulgarian Roma. The genetic support ranges from linkage in the largest family (LOD = 8.3) to three confirmed de novo mutations. We show that mRNA in the fibroblasts of affected individuals escapes nonsense-mediated decay and thus leads to the expression of truncated proteins; in addition, concentrations of the full-length protein are reduced in comparison to those in controls. This suggests either a dominant-negative effect or haploinsufficiency. UBAP1 links endosomal trafficking to the ubiquitination machinery pathways that have been previously implicated in HSPs, and UBAP1 provides a bridge toward a more unified pathophysiology.

Resumen: Introducción: La expansión de los estudios genéticos está transformando la práctica de la Neurología y enfrenta a los servicios clínicos con nuevos retos, como la articulación del asesoramiento genético. La amplitud de los conocimientos tanto clínicos como moleculares precisos, así como la necesidad de una evaluación psicológica y apoyo familiar, especialmente en los análisis predictivos y planificación reproductiva, hacen necesario un enfoque multidisciplinar. Desarrollo: Las características principales de las enfermedades neurodegenerativas de base genética son el elevado nivel de especialización requerido —por tratarse de enfermedades poco comunes y de difícil diagnóstico— junto con su carácter generalmente progresivo, la ausencia de tratamientos eficaces, la problemática generada por la posibilidad de estudios predictivos y la interpretación de los resultados genéticos. El objetivo del asesoramiento genético es proporcionar la información suficiente y objetiva para que cada individuo pueda tomar sus propias decisiones sobre el estudio genético. Debe incluir la evaluación de aspectos psicológicos y de comunicación familiar. El programa PICOGEN del Hospital Clinic de Barcelona para el análisis y asesoramiento genético en demencias es un buen ejemplo de una estrategia integrada capaz de abordar esta nueva situación asistencial en Neurología. Lamentablemente, este programa es una excepción en España y los pacientes con enfermedades neurogenéticas y sus familias no tienen garantizada habitualmente una asistencia adecuada. Conclusiones: El asesoramiento genético es un acto clínico per se, que precisa de un espacio, tiempo y recursos suficientes. Implica una participación multidisciplinar, atención a los aspectos psicológicos y familiares y no se puede llevar a cabo correctamente en el seno de una consulta rutinaria estándar de Neurología. Es necesaria una legislación que garantice la adecuada articulación del asesoramiento genético en nuestro país con criterios de calidad y equidad. Esto incluye la regulación de la formación de los profesionales necesarios, la clarificación de competencias y la dotación de recursos a las instituciones para el desarrollo de estos programas. Abstract: Introduction: The generalization of genetic studies is transforming the practice of Neurology and confronts the clinical departments with new challenges, such as the organization of genetic counseling. The requirement of specialized knowledge, both clinical and molecular, as well as the need for psychological evaluation and family support, especially for predictive testing and reproductive planning, makes a multidisciplinary approach mandatory. Development: The main characteristics of genetic neurodegenerative diseases are the high level of required specialization – since these disorders are often rare and of difficult diagnosis – together with a generally progressive course, unavailability of effective treatment, the issues generated by predictive testing and the interpretation of genetic testing. The aim of genetic counseling is to provide sufficient and objective information for each individual to make their own decision on genetic testing. It must touch upon psychological aspects and family communication. The PICOGEN program from the Clinic Hospital in Barcelona for genetic testing and counseling of dementias is a good example of integrated strategy capable of managing this new clinical scenario in neurology. Unfortunately, this program is an exception in Spain and the patients with neurogenetic disorders and their families usually do not have guaranteed access to an appropriate care. Conclusions: Genetic counseling is a unique clinical activity that requires provision of enough time, space and resources to be developed. It implies multidisciplinary participation, due attention to psychological and family issues, and cannot be carried out adequately in a routine Neurology clinic. Legislation is needed to promote a correct articulation of genetic counseling in our country with guarantee of quality and equity. This includes training of the necessary health professionals, clarification of competences and provision of resources to the institutions for the development of such programs. Palabras clave: Análisis genéticos, Asesoramiento genético, Neurogenética, Legislación, Enfermedades raras, Test predictivos, Keywords: Genetic tests, Genetic counseling, Neurogenetics, Legislation, Rare disorders, Predictive testing

Introduction: The generalization of genetic studies is transforming the practice of Neurology and confronts the clinical departments with new challenges, such as the organization of genetic counselling. The requirement of specialized knowledge, both clinical and molecular, as well as the need for psychological evaluation and family support, especially for predictive testing and reproductive planning, makes a multidisciplinary approach mandatory. Development: The main characteristics of genetic neurodegenerative diseases are the high level of required specialization - since these disorders are often rare and of difficult diagnosis - together with a generally progressive course, unavailability of effective treatment, the issues generated by predictive testing and the interpretation of genetic testing. The aim of genetic counselling is to provide sufficient and objective information for each individual to make their own decision on genetic testing. It must touch upon psychological aspects and family communication. The PICOGEN program from the Clinic Hospital in Barcelona for genetic testing and counselling of dementias is a good example of integrated strategy capable of managing this new clinical scenario in neurology. Unfortunately, this program is an exception in Spain and the patients with neurogenetic disorders and their families usually do not have guaranteed access to an appropriate care. Conclusions: Genetic counselling is a unique clinical activity that requires provision of enough time, space and resources to be developed. It implies multidisciplinary participation, due attention to psychological and family issues, and cannot be carried out adequately in a routine Neurology clinic. Legislation is needed to promote a correct articulation of genetic counselling in our country with guarantee of quality and equity. This includes training of the necessary health professionals, clarification of competences and provision of resources to the institutions for the development of such programs. Resumen: Introducción: La expansión de los estudios genéticos está transformando la práctica de la Neurología y enfrenta a los servicios clínicos con nuevos retos, como la articulación del asesoramiento genético. La amplitud de los conocimientos tanto clínicos como moleculares precisos, así como la necesidad de una evaluación psicológica y apoyo familiar, especialmente en los análisis predictivos y planificación reproductiva, hacen necesario un enfoque multidisciplinar. Desarrollo: Las características principales de las enfermedades neurodegenerativas de base genética son el elevado nivel de especialización requerido —por tratarse de enfermedades poco comunes y de difícil diagnóstico— junto con su carácter generalmente progresivo, la ausencia de tratamientos eficaces, la problemática generada por la posibilidad de estudios predictivos y la interpretación de los resultados genéticos. El objetivo del asesoramiento genético es proporcionar la información suficiente y objetiva para que cada individuo pueda tomar sus propias decisiones sobre el estudio genético. Debe incluir la evaluación de aspectos psicológicos y de comunicación familiar. El programa PICOGEN del Hospital Clínic de Barcelona para el análisis y asesoramiento genético en demencias es un buen ejemplo de una estrategia integrada capaz de abordar esta nueva situación asistencial en Neurología. Lamentablemente, este programa es una excepción en España y los pacientes con enfermedades neurogenéticas y sus familias no tienen garantizada habitualmente una asistencia adecuada. Conclusiones: El asesoramiento genético es un acto clínico per se, que precisa de un espacio, tiempo y recursos suficientes. Implica una participación multidisciplinar, atención a los aspectos psicológicos y familiares y no se puede llevar a cabo correctamente en el seno de una consulta rutinaria estándar de Neurología. Es necesaria una legislación que garantice la adecuada articulación del asesoramiento genético en nuestro país con criterios de calidad y equidad. Esto incluye la regulación de la formación de los profesionales necesarios, la clarificación de competencias y la dotación de recursos a las instituciones para el desarrollo de estos programas. Keywords: Genetic tests, Genetic counselling, Neurogenetics, Legislation, Rare disorders, Predictive testing, Palabras clave: Análisis genéticos, Asesoramiento genético, Neurogenética, Legislación, Enfermedades raras, Test predictivos

The Spanish and Portuguese ISFG Working Group (GEP-ISFG) carried out a collaborative exercise in order to asses the performance of two Y chromosome STR tetraplexes, which include the loci DYS461, GATA C4, DYS437 and DYS438 (GEPY I), and DYS460, GATA A10, GATA H4 and DYS439 (GEPY II). The groups that reported correct results in all the systems were also asked to analyse a population sample in order to evaluate the informative content of these STRs in different populations. A total of 1020 males out of 13 population samples from Argentina, Brazil, Costa Rica, Macao, Mozambique, Portugal and Spain were analysed for all the loci included in the present study. Haplotype and allele frequencies of these eight Y-STRs were estimated in all samples. The lowest haplotype diversity was found in the Lara (Argentina) population (95.44%) and the highest (99.90%) in Macao (China). Pairwise haplotype analysis showed the relative homogeneity of the Iberian origin samples, in accordance with what was previously found in the European populations for other Y-STR haplotypes (http://www.ystr.org). As expected, the four non-Caucasian samples, Macao (Chinese), Mozambique (Africans), Costa Rica (Africans) and Argentina (Lara, Amerindians), show highly significant Φst values in the pairwise comparisons with all the Caucasian samples. © 2003 Elsevier Ireland Ltd. All rights reserved.

A set of seven common Y-chromosome specific microsatellites has been used in the present report to type 308 individuals of 16 African population groups from Mozambique. These microsatellites include the DYS19, DYS390, DYS391, DYS392, DYS393, DYS389I and DYS389II systems. The population structure was analysed and therefore genetic distances and several diversity indices were computed and compared with other populations around the world. The results obtained in the present study show that these populations share common characteristics with other available Bantu-speaking African population groups and clear differences with non-African ones. The combination of the analysis of Y-chromosome STRs with other more slowly mutating Y-chromosome polymorphisms (biallelic markers), mtDNA sequences and autosomal data for the same populations, will allow the analysis of human evolution in paternal lineages in different time scales. The forensic implications of these results are discussed. D 2003 Elsevier Science B.V. All rights reserved.

A novel methodology based on PCR monitoring on-line with fluorescent formats using the LightCycler for Y chromosome SNP typing is proposed. The main advantages of the system are the time necessary for the analysis (which is around 20 min), the robustness and the accuracy of the method and especially its sensitivity, which permits the detection of the male component in male-female mixtures up to 1:300 for some of the SNPs. Singleplexes of four different SNPs (M9, sY81, SRY-1532 and SRY-2627) as well as two duplexes (M9 and sY81 on the one hand and SRY-1532 and SRY-2627 on the other) were efficiently implemented. A simultaneous amplification and analysis of the four SNPs is also possible. It seems difficult with the current methodology to implement more than a quadruplex.

In last years, interest in Single Nucleotide Polymorphism (SNP) has increased due to their numerous applications: in medical genetics, in human and evolutionary genetics but also in forensic field. Polymorphisms placed in the mitochondrial genome are particularly important in a forensic context in part due to the fact that it is in high copy number per cell. Consequently, mtDNA is especially useful to the study of degraded samples with little or no nuclear DNA as being old skeletal remains and hair shafts. On the other hand, mtDNA SNPs have demonstrate its usefulness for human population studies. The development of new methodologies for high-throughput SNPs analysis is one of the most promising areas in genetics. Here, we describe a rapid and robust assay to simultaneously genotype 17 SNPs of mitochondrial DNA by minisequencing reaction using SNaPshot (Applied Biosystems). The methodology here described shows high accuracy and sensitivity, and avoid the use of alternative time-consuming classical strategies (i.e. RFLP typing) and the requirement of high quantities of DNA template. D 2003 Elsevier B.V. All rights reserved.

In order to assess the microgeographic heterogeneity of Y chromosome lineage's distribution in the north-western part of Iberian Peninsula, 409 male samples from the five districts of Northern Portugal and two districts of Southern Galicia were typed for 15 Y chromosome microsatellite markers. The results suggest that, in NW Iberia, barriers other than political were more important in shaping present Y chromosome lineage substructuring.