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BACKGROUND: Pathogenic variants of the lysine acetyltransferase 6A or KAT6A gene are associated with a newly identified neurodevelopmental disorder characterized mainly by intellectual disability of variable severity and speech delay, hypotonia, and heart and eye malformations. Although loss of function (LoF) mutations were initially reported as causing this disorder, missense mutations, to date always involving serine residues, have recently been associated with a form of the disorder without cardiac involvement. RESULTS: In this study we present five new patients, four with truncating mutations and one with a missense change and the only one not presenting with cardiac anomalies. The missense change [p.(Gly359Ser)], also predicted to affect splicing by in silico tools, was functionally tested in the patient's lymphocyte RNA revealing a splicing effect for this allele that would lead to a frameshift and premature truncation. CONCLUSIONS: An extensive revision of the clinical features of these five patients revealed high concordance with the 80 cases previously reported, including developmental delay with speech delay, feeding difficulties, hypotonia, a high bulbous nose, and recurrent infections. Other features present in some of these five patients, such as cryptorchidism in males, syndactyly, and trigonocephaly, expand the clinical spectrum of this syndrome.

Fabry disease (FD) is a rare, X-linked disorder caused by mutations in the GLA gene encoding the enzyme alpha-galactosidase A. Complete or partial deficiency in this enzyme leads to intracellular accumulation of globotriaosylceramide (Gb3) and other glycosphingolipids in many cell types throughout the body, including the kidney. Progressive accumulation of Gb3 in podocytes, endothelial cells, epithelial cells, and tubular cells contribute to the renal symptoms of FD, which manifest as proteinuria and reduced glomerular filtration rate leading to renal insufficiency. A correct diagnosis of FD, although challenging, has considerable implications regarding treatment, management, and counseling. The diagnosis may be confirmed by demonstrating the enzyme deficiency in males and by identifying the specific GLA gene mutation in male and female patients. Treatment with enzyme replacement therapy, as part of the therapeutic strategy to prevent complications of the disease, may be beneficial in stabilizing renal function or slowing its decline, particularly in the early stages of the disease. Emergent treatments for FD include the recently approved chaperone molecule migalastat for patients with amenable mutations. The objective of this report is to provide an updated overview on Fabry nephropathy, with a focus on the most relevant aspects of its epidemiology, diagnosis, pathophysiology, and treatment options. (C) 2018 The Author(s) Published by S. Karger AG, Basel.

El término trastornos del espectro autista (TEA) agrupa cinco cuadros clínicos según el DSM-IV-TR, ocho si seguimos la Clasificación CIE-10 de la Organización Mundial de la Salud. Todos ellos se caracterizan por dificultades cualitativas de interacción social, con falta de empatía y reciprocidad social, incapacidad para reconocer y responder a gestos y expresiones, dificultades en la comunicación y falta de flexibilidad en razonamientos y comportamientos, con un repertorio restringido, estereotipado y repetitivo de actividades e intereses. Se trata de un trastorno prevalente, que predomina en varones y cuyos síntomas por lo general son evidentes entre los 18 y los 24 meses de edad; pese a ello es habitual que ocurra retraso en el diagnóstico. Desde Atención Primaria se ha de promover una intervención precoz mediante la vigilancia longitudinal del DPM, la realización de cribado sistemático entre los 18-24 meses de edad (M-CHAT) y considerando especialmente las preocupaciones expresadas por los padres como importante signo de alarma. El diagnóstico definitivo será llevado a cabo por un equipo multidisciplinar experto en los TEA que emplearán herramientas diagnósticas más específicas como ADI-R y ADOS. Existe evidencia de que las intervenciones son más efectivas cuando se inician precozmente, entre los 2 y los 4 años de edad. Además de lo anterior se han de atender los problemas médicos asociados, conocer las intervenciones farmacológicas y no farmacológicas para los comportamientos problemáticos y ofrecer formación y apoyo a las familias, las cuales han de conocer la existencia de terapias controvertidas, no sustentadas en evidencias científicas, a fin de que actúen con cautela frente a las mismas. The term, autistic spectrum disorder (ASD) groups 5 clinical conditions according to the DSM-IV-TR, eight if we follow the ICD-10 Classification of the World Health Organisation. All of them are characterised by qualitative social interaction difficulties, with lack of empathy and social reciprocity, inability to recognise and respond to gestures or expressions, communication difficulties, lack of flexibility in reasoning and behaviour, with a restricted, stereotyped and repetitive activities and interests. It is a prevalent disorder, which predominates in males and the symptoms are gene-rally evident between 18 and 24 months of age, this being a reason for the delay in diagnosis. An early intervention program must be introduced to monitor PSD over the longterm, performing systematic screening between 18-24 months of age (M-CHAT) and in particular, taking into account the concerns expressed by the parents as an important sign of alarm. The definitive diagnosis will be made by a multidisciplinary team expert in ASD, who will use more specific diagnostic tools like ADI-R and ADOS. There is evidence that interventions are more effective when started early, between 2 and 4 years of age. As well as all this, the associated medical problems have to be attended to. We must know the pharmacological and non-pharmacological interventions for problematic behaviours, and offer training and support ,to the families, who should be aware of controversial treatments, not supported by scientific evidence, so that they may act with caution with those.

The aim of this paper is to investigate heritable factors that might be related to the recognised genetic susceptibility for developing Paget's disease of bone (PD). This was a hospital-based, case-control study of a systematically selected group of PD patients and a group of controls drawn from the same health setting. In these populations we assessed surname pattern, parental consanguinity and constitutional physical traits. In a separate case-control analysis, genetically-based features and pathological traits of interest for genetic inference in 43 demonstrated familial cases were then compared to those in 24 sporadic cases. Results showed coincidence of three or four surnames (Odds Ratio [OR] = 5.6; 95% CI = 1.7-18.5), degree of parental consanguinity (OR = 4.1; 95% CI = 2.1-1.8), and green or blue eye colour (OR = 1.5; 95% CI = 1.1-2.1) were significantly associated with PD. Comparison of proven familial and sporadic PD cases showed that the former had a stronger association with Monckeberg-type vascular calcifications (32% vs. 4%; p = 0.02), percentage of skeleton affected (13.1 vs. 9.0), and green and blue eye colour (82% vs. 25%; p = 0.006), with Monckeberg-type vascular calcifications being the main variable of interest (OR = 30.9; 95% CI = 12.75-347.00) in the multivariate analysis. In conclusion, heritable factors are crucial in the pathogenesis of PD and, in line with other data sources, might account for the ethnic predisposition observed in different countries.

The EuroBioBank (EBB) network (www.eurobiobank.org) is the first operating network of biobanks in Europe to provide human DNA, cell and tissue samples as a service to the scientific community conducting research on rare diseases (RDs). The EBB was established in 2001 to facilitate access to RD biospecimens and associated data; it obtained funding from the European Commission in 2002 (5th framework programme) and started operation in 2003. The set-up phase, during the EC funding period 2003-2006, established the basis for running the network; the following consolidation phase has seen the growth of the network through the joining of new partners, better network cohesion, improved coordination of activities, and the development of a quality-control system. During this phase the network participated in the EC-funded TREAT-NMD programme and was involved in planning of the European Biobanking and Biomolecular Resources Research Infrastructure. Recently, EBB became a partner of RD-Connect, an FP7 EU programme aimed at linking RD biobanks, registries, and bioinformatics data. Within RD-Connect, EBB contributes expertise, promotes high professional standards, and best practices in RD biobanking, is implementing integration with RD patient registries and 'omics' data, thus challenging the fragmentation of international cooperation on the field. EBB thanks EURORDIS for administrative support, Fondazione Telethon for administrative and financial support, the EC for providing funds (grants: FP5 EuroBioBank, contract N. 02769; FP6 TREAT-NMD, contract N. 036825; and FP7 RD-Connect, grant agreement N. 305444), and AFM for the vision of the network and for encouraging the network to get together. EBB gratefully acknowledges patients and collaborating clinicians/researchers for contributing samples and data to the network, and biobank staffs for running the EBB biobanks. The MRC support to the biobank in London and Newcastle is also gratefully acknowledged. Sí