Dietary treatment in Glutaric Aciduria Type I

• January 31st, 2012

Strauss et al. published an article describing the effects of a lysine-free, arginine-rich formula for the treatment  of Glutaric Aciduria Type I.  This successful treatment strategy takes advantage of the kinetics of the y+ blood brain barrier transporter, and presumably limits lysine transport into the CNS. They conclude that monitoring the ratio between lysine and arginine could be a successful strategy for treatment in GAI. This represents an exciting development in the treatment of a devastating disorder.  (Strauss et al., Mol Genet and Metab 104 (2011) 93-10)

Hilary Vernon, MD PhD

http://dx.doi.org/10.1036/ommbid.123

New treatments for Angelman syndrome?

• January 31st, 2012

Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Huang HS et al. Nature. 2011 Dec 21.
Angelman syndrome is a genetic disorder characterized by severe developmental delay, severe speech impairment, gait ataxia and/or tremulousness of the limbs, as well as typical behaviour. It is an imprinting disorder caused by changes in the maternal allele of UBE3A gene. In neurons, the paternal allele of UBE3A is intact but epigenetically silenced. This study explored the possibility that Angelman syndrome could be treated by activating this silenced allele to restore functional UBE3A protein. Using an unbiased, high-content screen in primary cortical neurons from mice (AS animal model), Huang et al. identified 12 topoisomerase I inhibitors and 4 topoisomerase II inhibitors that unsilence the paternal UBE3A allele. This study also showed that the unsilenced paternal allele produces a functional protein. Topoisomerase inhibitors appear to regulate UBE3A gene expression through a transcriptional mechanism (not by affecting the methylation status). The in vivo experiments performed on adult mice suggest that transient topoisomerase inhibition may have long-standing effects on gene expression. This is an example of regaining gene function without doing gene therapy. The researchers have not yet examined the effect of treatment on behavior of mice.

Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Huang et al. Nature. 2011 Dec 21;481(7380):185-9. PMID: 22190039

posted by Yannis Trakadis MD, MSc

Mutations in SRCAP, Encoding SNF2-Related CREBBP Activator Protein, Cause Floating-Harbor Syndrome.

• January 30th, 2012

Hood et al, are reporting in the AJHG that SRCAP is causing Floating-Harbor Syndrome. Exome sequencing in five unrelated individuals identified mutations in SRCAP ; all are tightly clustered within a small (111 codon) region of the final exon. The results were further verified by identifying mutations in 8 more patients. In all the instances in which parental DNA was available, all mutations have been shown to be de novo. SRCAP is an SNF2-related chromatin-remodeling factor that serves as a coactivator for CREB-binding protein (CREBBP is the major cause of Rubinstein-Taybi syndrome). The mutations are predicted to abolish three C-terminal AT-hook DNA-binding motifs while leaving the CBP-binding and ATPase domains intact. These findings show that SRCAP mutations are the major cause of Floating-Harbor Syndrome and offer an explanation for the clinical overlap between Floating-Harbor Syndrome and Rubinstein-Taybi syndrome.

Periklis Makrythanasis, MD, PhD

Hood et al, Am J Hum Genet. 2012 Jan 18. [Epub ahead of print]

OMMBID Chapter 248 : Rubinstein-Taybi Syndrome

Evidence that mutations in EZH2 cause Weaver syndrome

• January 23rd, 2012

Gibson et al and Tatton-Brown K et al are reporting that enhancer of zeste homolog 2 (EZH2) is the cause of Weaver syndrome. In the first case, trio-based exome sequencing looking for de novo mutations was used to analyze two families affected by Weaver syndrome, including one of the original families reported in 1974, while in the second 4 affected non-related individuals were sequenced and the result was further confirmed by identifying  EZH2 mutations at 15/300 individuals with overgrowth syndromes. EZH2 encodes a member of the Polycomb-group (PcG) family which is involved in maintaining the transcriptional repressive state of genes over successive cell generations (GeneCards) and the presented findings provide further links between histone modifications and the regulation of human growth.

Periklis Makrythanasis, MD, PhD

Gibson et al, Am J Hum Genet. 2012 Jan 13;90(1):110-8

Tatton-Brown K et al, Oncotarget. 2011 Dec 21. [Epub ahead of print]

Glycerol-3-Phosphate Dehydrogenase deficiency

• January 12th, 2012

Basel-Vanagaite L. et al. Transient Infantile Hypertriglyceridemia, Fatty Liver, and Hepatic Fibrosis Caused by Mutated GPD1, Encoding Glycerol-3-Phosphate Dehydrogenase 1. Am J Hum Genet. 2012 Jan 4

In several individuals with childhood hypertriglyceridemia followed by liver fibrosis, this group identified mutations in GDP1, encoding Glycerol-3-Phosphate Dehydrogenase 1. The enzyme GPD1 reversibly converts glycerol-3-phosphate (G3P) in dihydroxyacetone phosphate (DHAP). The accumulation of G3P in this disease might lead to increased G3P to triglyceride conversion. Alternatively, at a later age, the accumulation of DHAP might be toxic for the liver. More functional studies will be required to understand the precise pathophysiology of this disease.

Posted by Philippe Campeau, MD

Hyperekplexia

• January 4th, 2012

On our clinical service, we recently encountered an infant with generalized stiffness and considered the diagnosis of hyperekplexia. Hyperekplexia is a disorder characerized by generalized stiffness in the neonatal period which improves over time, an overactive startle reflex, and a period of generalized stiffness following the startle response. We found that this diagnosis can be difficult to make, and in particular can be mistaken for seizures. Some diagnostic clues that were useful to us included an exaggerated head-retraction reflex, and a clinical response to clonazepam. 5 genes are known to be associated with hyperekplexia, the most common being GLRA1. A good literature review of this rare disorder was recently published by Mineyko, Can J Neurol Sci. 2011 May;38(3):411-6.

Hilary Vernon, MD PhD

http://dx.doi.org/10.1036/ommbid.239

MtDNA depletion and elevations in S-adenosylmethionine

• December 25th, 2011

Mudd et al. (Mol Genet Metab. 2011 Nov 12.) reported 2 patients with mtDNA depletion syndrome and elevations in S-adenosylmethionine and methionine. After careful investigation, they conclude that these analytes are not elevated due to additional primary defects in associated pathways (i.e. glycine N-methyltransferase). They  hypothesize that the primary mitochondrial defect disrupts the normal usage of AdoMet by mitochondria.

This is an interesting finding, and brings to attention the potential vast array of metabolic abnormalities that can be seen in primary mitochondrial defects in multiple seemingly unassociated pathways.

Hilary Vernon, MD PhD

http://dx.doi.org/10.1036/ommbid.127

Adenovirus-Associated Virus Vector–Mediated Gene Transfer in Hemophilia B

• December 23rd, 2011

Nathwani et al, report in the last issue of NEJM the results of a clinical trial consisting of an Adenovirus-Associated Virus (AAV) vector–mediated gene transfer in Hemophilia B. The cohort consisted of 6 patients who received low, intermediate or high doses of the vector. AAV-mediated expression of Factor IX (FIX) at 2 to 11% of normal levels was observed in all participants and was
roughly dose-dependent. 4 of the 6 discontinued FIX prophylaxis and remained free of spontaneous hemorrhage; in the other 2, the interval between prophylactic injections was increased. The two participants who received the high dose of vector received a short course of glucocorticoid therapy after increase of serum liver-enzyme levels which rapidly normalized aminotransferase
levels. The authors conclude that a single peripheral-vein infusion of the vector resulted in long-term expression of the FIX transgene at therapeutic levels without acute or long-lasting toxicity and is a critical step towards converting the severe bleeding phenotype into a mild form or reverse it completely.

Periklis Makrythanasis, MD, PhD

OMMBID Chapter 173: Hemophilia B: Factor IX Deficiency

Nathwani et al, N Engl J Med 2011;  365:2357-2365 December 22, 2011

Diagnostic Use of Next Generation Sequencing

• December 20th, 2011

Selmer et al report in EJMG, a family with 4 affected children who have been diagnosed with a mild form of Mucopolysaccharidosis IIIB through targeted next-generation sequencing of linked genomic regions. The patients aged 47-61, have been diagnosed with unspecified intellectual disability, retinitis pigmentosa, ataxia and cortical atrophy. Traditional investigations were not successful in providing an accurate diagnosis. This paper shows an example where the clinical use of next generation sequencing is used to correctly diagnose the mild form of a known genetic condition and demonstrates how new sequencing capabilities will help better understand the full phenotypic spectrum of the genetic disorders.

Periklis Makrythanasis MD, PhD

OMMBID Chapter 136: The Mucopolysaccharidoses

Adenosine Kinase Deficiency

• December 15th, 2011

Two siblings with developmental delay, liver dysfunction and hypermethioninemia were investigated by exome sequencing. A homozygous missense mutation was identified in adenosine kinase, which could explain the block in the methionine cycle. Additional families were identified, and the mutations affected enzymatic function. The mouse deficient in adenosine kinase, described previously, displays phenotypic similarities, and to date there is no specific treatment modality. The pathophysiology of the disease is most likely complex, since both the accumulation of the substrate (adenosine) and the deficiency of the product (AMP) are expected to be detrimental.

Bjursell MK et al. Am J Hum Genet. 2011 Oct 7;89(4):507-15

Posted by Philippe Campeau, MD