Severe neurometabolic phenotype in zebrafish with a C-terminal mutation.

Niemann Pick disease type C (NPC) is an autosomal recessive neurodegenerative lysosomal disorder characterized by an accumulation of lipids in different organs. Clinical manifestations can start at any age and include hepatosplenomegaly, intellectual impairment, and cerebellar ataxia. is the most common causal gene, with over 460 different mutations with heterogeneous pathological consequences.

Zebrafish Models of Autosomal Recessive Ataxias.

Autosomal recessive ataxias are much less well studied than autosomal dominant ataxias and there are no clearly defined systems to classify them. Autosomal recessive ataxias, which are characterized by neuronal and multisystemic features, have significant overlapping symptoms with other complex multisystemic recessive disorders. The generation of animal models of neurodegenerative disorders increases our knowledge of their cellular and molecular mechanisms and helps in the search for new therapies.

Zebrafish Models of Autosomal Dominant Ataxias.

Hereditary dominant ataxias are a heterogeneous group of neurodegenerative conditions causing cerebellar dysfunction and characterized by progressive motor incoordination. Despite many efforts put into the study of these diseases, there are no effective treatments yet. Zebrafish models are widely used to characterize neuronal disorders due to its conserved vertebrate genetics that easily support genetic edition and their optic transparency that allows observing the intact CNS and its connections.

Impaired proteasome activity and neurodegeneration with brain iron accumulation in FBXO7 defect.

Unlabelled: FBXO7 is implicated in the ubiquitin-proteasome system and parkin-mediated mitophagy. FBXO7defects cause a levodopa-responsive parkinsonian-pyramidal syndrome(PPS).

Methods: We investigated the disease molecular bases in a child with PPS and brain iron accumulation.

Characterising the phenotype and mode of inheritance of patients with inherited peripheral neuropathies carrying mutations.

Background: Mutations in the metalloendopeptidase () gene were initially identified as a cause of autosomal recessive Charcot-Marie-Tooth disease type 2 (CMT2). Subsequently, variants in were linked to other late-onset autosomal dominant polyneuropathies. Thus, our goal was to define the phenotype and mode of inheritance of patients carrying changes in .

An ontology-aware integration of clinical models, terminologies and guidelines: an exploratory study of the Scale for the Assessment and Rating of Ataxia (SARA).

Background: Electronic rating scales represent an important resource for standardized data collection. However, the ability to exploit reasoning on rating scale data is still limited. The objective of this work is to facilitate the integration of the semantics required to automatically interpret collections of standardized clinical data.

Prevalence of spinocerebellar ataxia 36 in a US population.

Objective: To assess the prevalence and clinical features of individuals affected by spinocerebellar ataxia 36 (SCA36) at a large tertiary referral center in the United States.

Methods: A total of 577 patients with undiagnosed sporadic or familial cerebellar ataxia comprehensively evaluated at a tertiary referral ataxia center were molecularly evaluated for SCA36. Repeat primed PCR and fragment analysis were used to screen for the presence of a repeat expansion in the gene.

A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia.

Advances in human genetics in recent years have largely been driven by next-generation sequencing (NGS); however, the discovery of disease-related gene mutations has been biased toward the exome because the large and very repetitive regions that characterize the non-coding genome remain difficult to reach by that technology. For autosomal-dominant spinocerebellar ataxias (SCAs), 28 genes have been identified, but only five SCAs originate from non-coding mutations. Over half of SCA-affected families, however, remain without a genetic diagnosis.

Transfer of genetic therapy across human populations: molecular targets for increasing patient coverage in repeat expansion diseases.

Allele-specific gene therapy aims to silence expression of mutant alleles through targeting of disease-linked single-nucleotide polymorphisms (SNPs). However, SNP linkage to disease varies between populations, making such molecular therapies applicable only to a subset of patients. Moreover, not all SNPs have the molecular features necessary for potent gene silencing.

Automated semantic annotation of rare disease cases: a case study.

Motivation: As the number of clinical reports in the peer-reviewed medical literature keeps growing, there is an increasing need for online search tools to find and analyze publications on patients with similar clinical characteristics. This problem is especially critical and challenging for rare diseases, where publications of large series are scarce. Through an applied example, we illustrate how to automatically identify new relevant cases and semantically annotate the relevant literature about patient case reports to capture the phenotype of a rare disease named cerebrotendinous xanthomatosis.

Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice.

Calcifications in the basal ganglia are a common incidental finding and are sometimes inherited as an autosomal dominant trait (idiopathic basal ganglia calcification (IBGC)). Recently, mutations in the PDGFRB gene coding for the platelet-derived growth factor receptor β (PDGF-Rβ) were linked to IBGC. Here we identify six families of different ancestry with nonsense and missense mutations in the gene encoding PDGF-B, the main ligand for PDGF-Rβ.

Summarizing phenotype evolution patterns from report cases.

The need to represent and manage time is implicit in several reasoning processes in medicine. However, this is predominantly obvious in the field of many neurodegenerative disorders, which are characterized by insidious onsets, progressive courses and variable combinations of clinical manifestations in each patient. Therefore, the availability of tools providing high level descriptions of the evolution of phenotype manifestations from patient data is crucial to promote early disease recognition and optimize the diagnostic process.

Querying phenotype-genotype relationships on patient datasets using semantic web technology: the example of Cerebrotendinous xanthomatosis.

Background: Semantic Web technology can considerably catalyze translational genetics and genomics research in medicine, where the interchange of information between basic research and clinical levels becomes crucial. This exchange involves mapping abstract phenotype descriptions from research resources, such as knowledge databases and catalogs, to unstructured datasets produced through experimental methods and clinical practice. This is especially true for the construction of mutation databases.

'Costa da Morte' ataxia is spinocerebellar ataxia 36: clinical and genetic characterization.

Spinocerebellar ataxia 36 has been recently described in Japanese families as a new type of spinocerebellar ataxia with motor neuron signs. It is caused by a GGCCTG repeat expansion in intron 1 of NOP56. Family interview and document research allowed us to reconstruct two extensive, multigenerational kindreds stemming from the same village (Costa da Morte in Galicia, Spain), in the 17th century.

Neurophysiological study in cerebrotendinous xanthomatosis.

Introduction: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal-recessive disease due to mutations of the 27α-hydroxylase. It is characterized by cataracts, xanthomas, and neurological manifestations. Polyneuropathy has been reported, although it is unclear whether it is axonal or demyelinating.

mtDNA mutations in tumors of the central nervous system reflect the neutral evolution of mtDNA in populations.

Mitochondrial DNA (mtDNA) instability has been observed in different types of cancer, including colorectal, breast, and gastric cancer. The relationship between the occurrence of such alteration and the nuclear microsatellite instability (nMI) status of the neoplastic cells remains controversial. In an attempt to clarify this issue, we sequenced the first and second mtDNA hypervariable regions, and typed the mitochondrial (CA)(n) dinucleotide polymorphism in 69 patients with primary tumors of the central nervous system (CNS), previously screened for nMI.