Oxidative stress & Wilson disease

• May 17th, 2012

A recent study by Bruha et al. suggests that increased oxidative stress may contribute significantly to the clinical manifestation of Wilson disease, an inherited disorder of copper disposition caused by an ATP7B transporter gene mutations.

Decreased serum antioxidant capacity in patients with Wilson disease is associated with neurological symptoms. Bruha et al. J Inherit Metab Dis. 2012 May;35(3):541-8. Epub 2011 Dec 3. PMID: 22139496

posted by Yannis Trakadis MD, MSc

Intranasal ERT in LSDs may bypass BBB

• May 13th, 2012

According to the study by Wolf et al. intranasal administration of α-l-iduronidase (IDUA) enzyme may be able to bypass the blood-brain barrier. This appears to be the case in IDUA-deficient mice after a single intranasal treatment with concentrated Aldurazyme®. Promising results in mice were also noted after intranasal treatment with an adeno-associated virus (AAV) vector expressing human IDUA. These experiments raise the possibility of non-invasive treatments for lysosomal storage disorders.

Lysosomal enzyme can bypass the blood-brain barrier and reach the CNS following intranasal administration. Wolf et al. Mol Genet Metab. 2012 May;106(1):131-4. PMID: 22420937 http://dx.doi.org/10.1016/j.ymgme.2012.02.006

posted by Yannis Trakadis MD, MSc

siRNA based drugs & vaccines?

• May 13th, 2012

Short interfering RNAs (siRNAs) are RNA strands designed to bind to target strands of mRNA and knock down the expression of targeted genes, thus preventing the synthesis of the respective proteins. Special interest in recent years about using siRNAs to target key disease proteins has been suppressed due to the difficulty of having the siRNAs enter the cells, a necessary step of this process. RNA is negatively charged and repelled by the negatively charged surface of the cells. Recent developments, summarized by Robert Service in Science, show that packing hundreds of copies of siRNA strands into a tight ball (nanoparticle) may overcome this limitation and lead to novel treatments and vaccines. This is based on the fact that multiple positively charged cell surface proteins called scavenger proteins bind and engulf the RNA ball into the cell.   

American Chemical Society Spring Meeting. Nanoparticles offer ‘open sesame’ keys to new drugs and vaccines. Service RF. Science. 2012 Apr 20;336(6079):292. PMID: 22517836

posted by Yannis Trakadis MD, MSc

Evidence of non-random mutation rates suggests an evolutionary risk management strategy

• May 3rd, 2012

Martincorena et al are reporting in Nature evidence challenging the tenet that mutations occur randomly and then selection governs whether they are fixed or not. By comparing 34 E.coli genomes  and after excluding usual causes of difference in mutation rate (codon usage bias, mRNA-folding stability in the 5´, GC content and within-species homologous recombination)  the authors observe that the neutral mutation rate varies by more than an order of magnitude across 2.659 genes. The mutation rate is lower at highly expressed genes implying the presence of unknown compensatory mechanisms. They go a step further showing that purifying, rather than positive, selection has driven the evolution of the local point mutation rate in order to reduce risk of deleterious mutations and possibly increase the rate of non-deleterious mutations thus increasing the adaptive potential.

Periklis Makrythanasis, MD, PhD

Martincorena I, Seshasayee AS, Luscombe NM.; Nature. 2012 Apr 22. doi: 10.1038/nature10995. [Epub ahead of print]

OMMBID Chapter 13: The Nature and Mechanisms of Human Gene Mutation

Tyrosinemia and creatine kinase

• April 30th, 2012

Tyrosinemia type 2 is an autosomal recessive disorder caused by mutations in the TAT gene (16q22.1) encoding tyrosine aminotransferase. Major clinical features include corneal lesions and hyperkeratotic skin plaques. In addition, there are well described neurological features including learning disabilities, tremor, ataxia and seizures. de Andrade et al. in Metab Brain Dis. 2011 Sep;26(3):221-7 offers in vitro and in vivo evidence to show that tyrosine inhibits creatine kinase in the cortex in a dose dependant manner, and they propose that this inhibition might contribute to the neurological phenotype of Tyrosinemia type 2. This work offers a unique target for treatment, and further emphasizes the importance of understanding the complex secondary biochemical effects of well described inborn errors of metabolism.

Hilary Vernon, MD PhD

http://dx.doi.org/10.1036/ommbid.102

2 methylbutyrylglycinuria

• April 30th, 2012

I was asked to see a baby with a positive newborn screen with an elevation in C5 and mild elevation in C4 interpreted as being consistent with 2-methylbutyrylglycinuria. This  is not a disorder I am familiar with, and the literature is somewhat scarce. While the first few reported patients had features such as autism or mental retardation,  multiple subsequently reported individuals with a biochemical phenotype of 2- methylbutyrylglycinuria had only a biochemical, and not a clinical phenotype. A particular mutation is somewhat common in the Hmong population, and appears to be clinically asymptomatic. Thus, it is unclear if 2-MBGuria will join the ranks of asymptomatic biochemical abnormalities, or truly has a phenotype in some affected individuals. A good review by Alfardan et al., was published in Mol Genet Metab. 2010 Aug;100(4):333-8.

Hilary Vernon, MD PhD

http://dx.doi.org/10.1036/ommbid.121

de novo mutations and autism

• April 14th, 2012

Sanders et al. completed whole-exome sequencing in 238 families from the Simons Simplex Collection (SSC). SSC is a comprehensively phenotyped autism spectrum disorders cohort consisting of pedigrees with two unaffected parents, an affected proband, and, in 200 families, an unaffected sibling. Based on the results of whole-exome sequencing of a total of 928 individuals Sanders et al. concluded that de novo single nucleotide variants in brain-expressed genes are associated with autism spectrum disorders and carry large effects.

De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Sanders et al. Nature. 2012 Apr 4. PMID: 22495306

posted by Yannis Trakadis MD, MSc

Extrachromosomal circular DNA: microDNA

• April 14th, 2012

Shibata et al. identified a new form of Extrachromosomal circular DNA (microDNA) in mouse tissues as well as human cell lines. These microDNAs are 200 to 400 bp long. Unlike formerly described Extrachromosomal circular DNA, they are not derived from repetitive sequences, transposable elements, or viral genomes. They are derived from unique nonrepetitive genomic sequences which are often associated with genes. Formation of these microDNA appears to be associated with microdeletions. The generation of microDNAs and microdeletions may be a source of individual-specific or somatic-clone–specific copy-number variations. Their role in functional differences between cells in a tissue remains to be explored.

Extrachromosomal microDNAs and chromosomal microdeletions in normal tissues. Shibata et al. Science. 2012 Apr 6;336(6077):82-6. Epub 2012 Mar 8. PMID: 22403181

posted by Yannis Trakadis MD, MSc

Autism

• April 12th, 2012

Campbell and colleagues found through a GWAS a significant association of autism spectrum disorder (ASD) with a SNP located in a gene-poor region of chromosome 5p14.1. They found that individuals who carry this ASD-associated SNP showed increased expression of  moesin pseudogene 1, antisense(MSNP1AS), a noncoding RNA encoded by the moesin pseudogene 1 (MSNP1). MSNP1AS is 94% identical and antisense to the X chromosome transcript of MSN, which encodes a protein (moesin) that regulates neuronal architecture. The MSNP1AS noncoding RNA bound to MSN, was found to be highly overexpressed (12.7-fold) in postmortem cerebral cortex of individuals with ASD, and could regulate levels of moesin protein in human cell lines (Sci Transl Med 4 April 2012: Vol. 4, Issue 128, p. 128ra40).

Posted by Nicola Brunetti-Pierri, MD, FACMG

SLOS and oxidative metabolites

• March 31st, 2012

Smith-Lemli-Opitz Syndrome (SLOS) is the most common disorder of sterol synthesis, and is caused by a defect in 7-dehydrocholesterol reductase. Biochemical markers for this disease include increased 7- and 8-dehydrocholesterol. Xu et al. have recently described aberrant oxidative metabolites of 7-dehydrocholesterol (7-DHC) including 3β,5α-dihydroxycholest-7-en-6-one (DHCEO).This group found that the oxidative metabolite DHCEO leads to dysregulated differentiation and arborization of cortical neurons. They suggest that anti-oxidant therapy is a potential therapy for some of the features of SLOS. (Neurobiol Dis. 2012 Mar;45(3):923-9.)

Hilary Vernon, MD PhD

http://dx.doi.org/10.1036/ommbid.289