Abstract Inborn errors of metabolism are predominantly autosomal-recessive disorders, but several follow an X-linked pattern of inheritance. They are called X-linked recessive, if the female carriers are asymptomatic, and are called X-linked dominant disorders, if almost all females are affected. Conditions, in which some females have symptoms while others are asymptomatic lifelong are simply referred to as X-linked. The aim of this review is to point out the variability in clinical manifestation of affected females in some X-linked metabolic disorders and to discuss on the basis of these examples possible mechanisms that may explain the broad phenotypic spectrum, such as the type of the underlying mutation, the issue of autonomous versus non-autonomous gene expression and the degree of skewing of X-inactivation. The use of the terms “X-linked dominant” and “X-linked recessive” will be discussed.

Abstract Next-generation sequencing (NGS) panels are used widely in clinical diagnostics to identify genetic causes of various monogenic disease groups including neurometabolic disorders and, more recently, lysosomal storage disorders (LSDs). Many new challenges have been introduced through these new technologies, both at the laboratory level and at the bioinformatics level, with consequences including new requirements for interpretation of results, and for genetic counseling. We review some recent examples of the application of NGS technologies, with purely diagnostic and with both diagnostic and research aims, for establishing a rapid genetic diagnosis in LSDs. Given that NGS can be applied in a way that takes into account the many issues raised by international consensus guidelines, it can have a significant role even early in the course of the diagnostic process, in combination with biochemical and clinical data. Besides decreasing the delay in diagnosis for many patients, a precise molecular diagnosis is extremely important as new therapies are becoming available within the LSD spectrum for patients who share specific types of mutations. A genetic diagnosis is also the prerequisite for genetic counseling, family planning, and the individual choice of reproductive options in affected families.

Abstract The Fabry Outcome Survey (FOS) is an international long-term observational registry sponsored by Shire for patients diagnosed with Fabry disease who are receiving or are candidates for therapy with agalsidase alfa (agalα). Established in 2001, FOS provides long-term data on agalα safety/efficacy and collects data on the natural history of Fabry disease, with the aim of improving clinical management. The FOS publications have helped establish prognostic and severity scores, defined the incidence of specific disease variants and implications for clinical management, described clinical manifestations in special populations, confirmed the high prevalence of cardiac morbidity, and demonstrated correlations between ocular changes and Fabry disease severity. These FOS data represent a rich resource with utility not only for description of natural history/therapeutic effects but also for exploratory hypothesis testing and generation of tools for diagnosis/management, with the potential to improve future patient outcomes.

Abstract In the last decades, it has become more and more evident that lysosomal storage disorders and common neurodegenerative diseases such as Alzheimer and Parkinson diseases have clinical, neuropathological, and genetic features in common, including lysosomal dysfunction and impaired autophagy. Patients with Gaucher and even carriers of Gaucher disease have an increased risk to develop Parkinson disease. Likewise, individuals who are heterozygous for a mutation of a gene that causes an adult form of neuronal ceroid lipofuscinosis are more likely to be affected by a form of frontotemporal dementia in their later life. A further example is the gene NAGLU encoding the enzyme α-N-acetylglucosaminidase, which is deficient in patients with mucopolysaccharidosis type IIIB. Mutations of the NAGLU gene have been observed in patients affected by an axonal neuropathy. An interesting unexpected finding was the link between stuttering and genes that are essential for the function of all lysosomal enzymes. This review will present some example of the association of lysosomal storage disorders and neurodegenerative disease and discuss possible pathogenic mechanisms that are common to both conditions. The understanding of the pathophysiology of the endosomal–lysosomal–autophagic system may help to develop drugs, which might provide benefit not only for patients with rare lysosomal storage disorders but also for individuals affected by more common diseases.

We now know a good deal about economic voting, but that knowledge comes mostly from research on high-income democracies, such as those in North America and Western Europe. Of course, there are serious relevant studies on low-income democracies, but they are largely of single-country design, frequently employing aggregate data. Multi-national, individual-level survey designs are all but non-existent. Here we examine a 13 - nation pool of current Latin American voting surveys. From estimation of a fully specified, and vigorously challenged, voting model, we conclude there are general, and rather strong, sociotropic retrospective economic voting effects. This finding is ofnormative, as well as scientific importance, indicating that governments in these low-income democracies cannot escape electoral sanction for the delivery of poor economic performance.

En la actualidad existe un amplio conocimiento acerca del voto económico; conocimiento que, en general, proviene de democracias desarrolladas (Norteamérica y Europa Occidental). Existen trabajos relevantes sobre democracias con niveles de ingresos bajos, pero basados en estudios de casos con datos agregados. Trabajos que incorporen diferentes países y que utilicen encuestas con datos individuales son prácticamente inexistentes. A partir de encuestas electorales, en el siguiente trabajo se examinan 13 países de América Latina de manera conjunta. Mediante la estimación de un modelo de voto altamente especificado y puesto a prueba rigurosamente, se concluye que hay efectos de voto económico sociotrópico retrospectivo generales y bastante fuertes. Este hallazgo posee importancia científica y normativa, indicando que los gobiernos en esas democracias no pueden escapar a la sanción electoral por los pobres resultados económicos.