Co-existence of Phenylketonuria and Fabry disease on a 3 year-old boy: case report

Background: The co-existence of two genetically distinct metabolic disorders in the same patient has rarely been reported. Phenylketonuria (PKU) is an inborn error of the metabolism resulting from a phenylalanine hydroxylase defi ciency. Fabry disease (FD) is an X-linked lysosomal storage disorder due to a defi ciency of the enzyme alpha-galactosidase A. Case presentation: We report a case of a 3-year-old boy affected by classic PKU and FD, both confi rmed by molecular data. The FD was suspected at the age of 21 months on the presence of non-specifi c GI symptoms (severe abdominal pain and periodically appearance of not specifi c episodes of gastroenteritis) apparently non related to PKU. Conclusion: This is the fi rst report of co-existence of FD and PKU, two different congenital inborn of metabolism and in consideration of the prevalence of each disease this chance association is a very unusual event. The co-existence of these diseases made very diffi cult the correct interpretation of clinical symptoms as lack of appetite, severe abdominal pain and non-specifi c gastroenteritis episodes. Furthermore, this case report helps to defi ne the early clinical phenotype of FD

Developing Product Label Information to Support Evidence-Informed Use of Vaccines in Pregnancy

Background: Product labelling information describing the use of vaccines in pregnancy continues to contain cautionary language even after clinical and epidemiological evidence of safety becomes available. This language raises safety concerns among healthcare providers who may hesitate to recommend vaccines during pregnancy. Purpose: To develop clear evidence-based language about vaccine safety and effectiveness in pregnancy for inclusion in vaccine product labels. Methods: We conducted a three-stage consensus-methods project with stakeholders, including: healthcare providers, vaccine regulators, industry representatives, and experts in public health, communication, law, ethics, and social sciences. Using qualitative and quantitative methods, we held a nominal group technique (NGT) meeting, followed by a Delphi survey, and then a consensus workshop with a subset of Delphi participants. We developed a methodological tool to analyse data for consensus. Principal results: Stakeholders (N = 14) at the NGT meeting drafted product label statements for evaluation in the Delphi survey. Survey participants (N = 41) provided feedback on statements for five hypothetical vaccines. Workshop participants (N = 27) initiated discussions that demonstrated a lack of awareness that the regulatory purpose of product labels is to provide a scientific summary of product-specific preclinical and clinical trial data. Each stage of this project built on earlier stages until we achieved strong consensus on the language, structure, and types of data that stakeholders wanted to include in inactivated influenza vaccine (IIV) and tetanus-diphtheria-acellular pertussis (Tdap) vaccine product labels in Canada. Conclusions: The revised statements for IIV and Tdap aligned with workshop participants’ goals that the product label be evidence-based, with a consistent structure and language that is easily understood by healthcare providers. Emergent methods uncovered stakeholder concerns about the regulatory purpose, content, and evidence used in product labels. Involving healthcare providers in the development and regular updating of product information could prevent interpretations of that information that contribute to vaccine hesitancy

Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice.

To gain insight into how mutant huntingtin (mHtt) CAG repeat length modifies Huntington's disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat lengths. We found repeat length-dependent transcriptional signatures to be prominent in the striatum, less so in cortex, and minimal in the liver. Coexpression network analyses revealed 13 striatal and 5 cortical modules that correlated highly with CAG length and age, and that were preserved in HD models and sometimes in patients. Top striatal modules implicated mHtt CAG length and age in graded impairment in the expression of identity genes for striatal medium spiny neurons and in dysregulation of cyclic AMP signaling, cell death and protocadherin genes. We used proteomics to confirm 790 genes and 5 striatal modules with CAG length-dependent dysregulation at the protein level, and validated 22 striatal module genes as modifiers of mHtt toxicities in vivo

Identification of Genetic Factors that Modify Clinical Onset of Huntington’s Disease

SummaryAs a Mendelian neurodegenerative disorder, the genetic risk of Huntington’s disease (HD) is conferred entirely by an HTT CAG repeat expansion whose length is the primary determinant of the rate of pathogenesis leading to disease onset. To investigate the pathogenic process that precedes disease, we used genome-wide association (GWA) analysis to identify loci harboring genetic variations that alter the age at neurological onset of HD. A chromosome 15 locus displays two independent effects that accelerate or delay onset by 6.1 years and 1.4 years, respectively, whereas a chromosome 8 locus hastens onset by 1.6 years. Association at MLH1 and pathway analysis of the full GWA results support a role for DNA handling and repair mechanisms in altering the course of HD. Our findings demonstrate that HD disease modification in humans occurs in nature and offer a genetic route to identifying in-human validated therapeutic targets in this and other Mendelian disorders.PaperCli

Population stratification may bias analysis of PGC-1α as a modifier of age at Huntington disease motor onset

Huntington’s disease (HD) is an inherited neurodegenerative disorder characterized by motor, cognitive and behavioral disturbances, caused by the expansion of a CAG trinucleotide repeat in the HD gene. The CAG allele size is the major determinant of age at onset (AO) of motor symptoms, although the remaining variance in AO is highly heritable. The rs7665116 SNP in PPARGC1A, encoding the mitochondrial regulator PGC-1α, has been reported to be a significant modifier of AO in three European HD cohorts, perhaps due to affected cases from Italy. We attempted to replicate these findings in a large collection of (1,727) HD patient DNA samples of European origin. In the entire cohort, rs7665116 showed a significant effect in the dominant model (p value = 0.008) and the additive model (p value = 0.009). However, when examined by origin, cases of Southern European origin had an increased rs7665116 minor allele frequency (MAF), consistent with this being an ancestry-tagging SNP. The Southern European cases, despite similar mean CAG allele size, had a significantly older mean AO (p < 0.001), suggesting population-dependent phenotype stratification. When the generalized estimating equations models were adjusted for ancestry, the effect of the rs7665116 genotype on AO decreased dramatically. Our results do not support rs7665116 as a modifier of AO of motor symptoms, as we found evidence for a dramatic effect of phenotypic (AO) and genotypic (MAF) stratification among European cohorts that was not considered in previously reported association studies. A significantly older AO in Southern Europe may reflect population differences in genetic or environmental factors that warrant further investigation

Candidate glutamatergic and dopaminergic pathway gene variants do not influence Huntington’s disease motor onset

Huntington’s disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. It is caused by the expansion of the HTT CAG repeat, which is the major determinant of age at onset (AO) of motor symptoms. Aberrant function of N-methyl-D-aspartate receptors and/or overexposure to dopamine has been suggested to cause significant neurotoxicity, contributing to HD pathogenesis. We used genetic association analysis in 1,628 HD patients to evaluate candidate polymorphisms in N-methyl-D-aspartate receptor subtype genes (GRIN2A rs4998386 and rs2650427, and GRIN2B rs1806201) and functional polymorphisms in genes in the dopamine pathway (DAT1 3′ UTR 40-bp variable number tandem repeat (VNTR), DRD4 exon 3 48-bp VNTR, DRD2 rs1800497, and COMT rs4608) as potential modifiers of the disease process. None of the seven polymorphisms tested was found to be associated with significant modification of motor AO, either in a dominant or additive model, after adjusting for ancestry. The results of this candidate-genetic study therefore do not provide strong evidence to support a modulatory role for these variations within glutamatergic and dopaminergic genes in the AO of HD motor manifestations

Low appendicular muscle mass is correlated with femoral neck bone mineral density loss in postmenopausal women

<p>Abstract</p> <p>Background</p> <p>After menopause, rapid bone mass loss occurs in response to hypoestrogenism. Several studies suggest that muscle mass and bone mineral density (BMD) are positively associated in postmenopausal women. Therefore, it may be assumed that postmenopausal low appendicular muscle mass (aMM) can increase BMD loss in a short period of time.</p> <p>Objective</p> <p>The purpose of this study was to assess relationship of aMM with femoral neck BMD in postmenopausal women.</p> <p>Methods</p> <p>Prospective, controlled clinical Trial including 64 women aged 45-70 years, who had not had their last menstruation for at least one year. Subjects were divided into two groups: low aMM (n = 32), and normal aMM (n-32). Femoral neck BMD and muscle mass were measured by DXA at baseline and after twelve months. Pairwise and independent t tests were used for data analysis.</p> <p>Results</p> <p>Baseline weight, BMI and muscle mass (total and appendicular) significantly differ between groups (p < 0.05). After twelve months, femoral neck BMD was significantly lower in the group with low aMM, whereas no significant difference was observed in the group with normal aMM (p < 0.05).</p> <p>Conclusion</p> <p>In postmenopausal women, low appendicular muscle mass is associated negatively with femoral neck BMD in a short period of time.</p

CAG repeat not polyglutamine length determines timing of Huntington’s disease onset

Variable, glutamine-encoding, CAA interruptions indicate that a property of the uninterrupted HTT CAG repeat sequence, distinct from the length of huntingtin’s polyglutamine segment, dictates the rate at which Huntington’s disease (HD) develops. The timing of onset shows no significant association with HTT cis-eQTLs but is influenced, sometimes in a sex-specific manner, by polymorphic variation at multiple DNA maintenance genes, suggesting that the special onset-determining property of the uninterrupted CAG repeat is a propensity for length instability that leads to its somatic expansion. Additional naturally occurring genetic modifier loci, defined by GWAS, may influence HD pathogenesis through other mechanisms. These findings have profound implications for the pathogenesis of HD and other repeat diseases and question the fundamental premise that polyglutamine length determines the rate of pathogenesis in the “polyglutamine disorders.

Epigenetic Dysregulation in Mesenchymal Stem Cell Aging and Spontaneous Differentiation

BACKGROUND: Mesenchymal stem cells (MSCs) hold great promise for the treatment of difficult diseases. As MSCs represent a rare cell population, ex vivo expansion of MSCs is indispensable to obtain sufficient amounts of cells for therapies and tissue engineering. However, spontaneous differentiation and aging of MSCs occur during expansion and the molecular mechanisms involved have been poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: Human MSCs in early and late passages were examined for their expression of genes involved in osteogenesis to determine their spontaneous differentiation towards osteoblasts in vitro, and of genes involved in self-renewal and proliferation for multipotent differentiation potential. In parallel, promoter DNA methylation and hostone H3 acetylation levels were determined. We found that MSCs underwent aging and spontaneous osteogenic differentiation upon regular culture expansion, with progressive downregulation of TERT and upregulation of osteogenic genes such as Runx2 and ALP. Meanwhile, the expression of genes associated with stem cell self-renewal such as Oct4 and Sox2 declined markedly. Notably, the altered expression of these genes were closely associated with epigenetic dysregulation of histone H3 acetylation in K9 and K14, but not with methylation of CpG islands in the promoter regions of most of these genes. bFGF promoted MSC proliferation and suppressed its spontaneous osteogenic differentiation, with corresponding changes in histone H3 acetylation in TERT, Oct4, Sox2, Runx2 and ALP genes. CONCLUSIONS/SIGNIFICANCE: Our results indicate that histone H3 acetylation, which can be modulated by extrinsic signals, plays a key role in regulating MSC aging and differentiation

Modification of Huntington's disease by short tandem repeats

Expansions of glutamine-coding CAG trinucleotide repeats cause a number of neurodegenerative diseases, including Huntington's disease (HD) and several of the spinocerebellar ataxias (SCAs). In general, age-at-onset of the polyglutamine diseases is inversely correlated with the size of the respective inherited expanded CAG repeat. Expanded CAG repeats are also somatically unstable in certain tissues, and age-at-onset of HD corrected for individual HTT CAG repeat length (i.e., residual age-at-onset), is modified by repeat instability-related DNA maintenance/repair genes as demonstrated by recent genome-wide association studies (GWAS). Modification of one polyglutamine disease (e.g., HD) by the repeat length of another (e.g., ATXN3, CAG expansions in which cause SCA3) has also been hypothesized. Consequently, we determined whether age-at-onset in HD is modified by the CAG repeats of other polyglutamine disease genes. We found that the CAG measured repeat sizes of other polyglutamine disease genes were polymorphic in HD participants but did not influence HD age-at-onset. Additional analysis focusing specifically on ATXN3 in a larger sample set (n = 1,388) confirmed the lack of association between HD residual age-at-onset and ATXN3 CAG repeat length. Additionally, neither our HD onset modifier GWAS single nucleotide polymorphism (SNP) data nor imputed short tandem repeat (STR) data supported involvement of other polyglutamine disease genes in modifying HD. By contrast, our GWAS based on imputed STRs revealed significant modification signals for other genomic regions. Together, our STR GWAS show that modification of HD is associated with STRs that do not involve other polyglutamine disease-causing genes, refining the landscape of HD modification and highlighting the importance of rigorous data analysis, especially in genetic studies testing candidate modifiers