GTPBP3 abnormalities and mitochondrial disease

Posted by & filed under New IEM.

GTPBP3 encodes for a modifier of a uridine located in the wobble position of several  mt-tRNA species. This base pair modification possibly has a role in the stabilization of tRNA-mRNA interactions.

Recently, Kopajtich et al (Am J Hum Genet. 2014 Dec 4;95(6):708-20. doi: 10.1016/j.ajhg.2014.10.017) described 11 patients in 9 families with compound heterozygous or homozygous mutations in GTPBP3. These patients had an array of features consistent with other disorders of mitochondrial dysfunction including: lactic acidosis, cardiomyopathy, decompensation with intercurrent illness, and encephalopathy. Through mechanistic studies on patient derived cell lines, thus group was able to show abnormalities in oxygen consumption rate and in mitochondrial protein synthesis, thus connecting the variants to mitochondrial functional defects.

Hilary Vernon

IDH2 deficiency in mice: D2- hydroxyglutarate is neurotoxic and cardiotoxic

Posted by & filed under Part 09: ORGANIC ACIDS.

Specific gain of function mutations in IDH2 cause D2-hydroxyglutaric aciduria, a disorder with severe effects on the central nervous system including infantile encephalopathy, seizures, and white matter abnormalities. Cardiomyopathy is also an important feature of this disorder.

Akbay et al. (Genes Dev. 2014 Mar 1;28(5):479-90. doi: 10.1101/gad.231233.113.) recently published a paper in which they described a conditional mouse model of IDH2 activation, and showed that induction of the mutant IDH2 expression in adult mice leads to dilated cardiomyopathy and white matter abnormalities in the brain. In addition, in utero activation of the mutant IDH2 resulted in a more severe phenotype. Notably, when the mutant gene is silenced, the cardiac abnormalities are improved. These findings provide evidence that inhibitors of mutant IDH2, such as are in development for cancer therapy, may have a role in the treatment of D2-hydroxyglutaric aciduria.

Hilary Vernon, MD PhD

Genomics to accelerate diagnosis of IEM

Posted by & filed under Part 06: DIAGNOSTIC APPROACHES, Tools.

Stranneheim et al. demonstrated how Massively parallel DNA sequencing (MPS) can aid in the diagnosis and early intervention of patients with Inborn Errors of Metabolism (IEM). Their method focuses on analysing pulsed whole genome sequence data in real time, using automated analysis combined with data reduction and parallelization. The genes targeted are 474 disease genes corresponding to IEM with a known genetic basis. (This database of genes/conditions is reportedly continuously updated.)

As proof-of-concept, two known patients were retrospectively analysed: their mutations were identified and presented to the clinical team after 15 and 18 hours from start of sequencing, respectively.

With the progressive decrease of MPS cost, IEM may be particularly amenable to such methodologies since irreversible damage often correlates with delays in diagnosis and intervention.

Rapid pulsed whole genome sequencing for comprehensive acute diagnostics of inborn errors of metabolism. Stranneheim et al. BMC Genomics. 2014 Dec 11;15:1090. PMID: 25495354

Posted by Yannis Trakadis, MD

HSCT transplantation in patients with CVID

Posted by & filed under Part 20: IMMUNE AND DEFENSE SYSTEMS.

Wehr et al explored the outcomes of hematopoietic stem cell transplantation (HSCT) in patients with Common variable immunodeficiency (CVID). Based on retrospective data collected from 14 centers worldwide, 25 patients with CVID, who received HSCT between 1993 and 2012, were identified. These patients’ ages ranged from 8 to 50 years at the time of transplantation. The overall survival rate was 48%, and the survival rate for patients undergoing transplantation for lymphoma was 83%. Graft-versus-host disease associated with infectious complications was the principal cause of death. In 92% of surviving patients, the condition constituting the indication for HSCT resolved.

In conclusion, HSCT in patients with CVID was successful in most surviving patients. However, due to the high mortality associated with the procedure, only patients who do not respond to immunoglobulin substitution and immunomodulatory drugs should be considered for HSCT.

Multicenter experience in hematopoietic stem cell transplantation for serious complications of common variable immunodeficiency. Wehr et al; the Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation and the European Society for Immunodeficiency. J Allergy Clin Immunol. 2015 Jan 14. pii: S0091-6749(14)01732-1.  PMID: 25595268

posted by Yannis Trakadis, MD

Statin treatment for FGFR3 skeletal dysplasia phenotypes.

Posted by & filed under Part 22: CONNECTIVE TISSUE.

A paper published in Nature in September 2014 suggests that statins could represent a medical treatment for infants and children with thanatophoric dysplasia type I (TD1) and achondroplasia (ACH) due to gain-of-function mutations in the fibroblast growth factor receptor 3 gene (FGFR3). The authors showed that statin treatment can rescue patient-specific induced pluripotent stem cell (iPSC) models and a mouse model of FGFR3 skeletal dysplasia. The chondrogenic differentiation of TD1 iPSCs and ACH iPSCs resulted in the formation of degraded cartilage. We found that statins could correct the degraded cartilage in both TD1 and ACH chondrocytes. Importantly, treatment of ACH model mice with statin led to a significant recovery of bone growth.

Posted by Nicola Bruneti-Pierri

Anti–microRNA-21 oligonucleotides prevent Alport nephropathy

Posted by & filed under Part 24: KIDNEY.

MicroRNA-21 (miR-21) contributes to the pathogenesis of fibrogenic diseases in multiple organs, including the kidneys. Highly specific oligonucleotides that distribute to the kidney and inhibit miR-21 function when administered subcutaneously have been recently developed. In a murine model of Alport nephropathy, miR-21 silencing resulted in milder kidney disease, with minimal albuminuria and dysfunction. miR-21 silencing dramatically improved survival of Alport mice and reduced glomerulosclerosis, interstitial fibrosis, tubular injury, and inflammation. Anti–miR-21 enhanced PPAR?/retinoid X receptor (PPAR?/RXR) activity and downstream signaling pathways in glomerular, tubular, and interstitial cells. Inhibition of miR-21 was protective against TGF-?–induced fibrogenesis and inflammation in glomerular and interstitial cells, likely as the result of enhanced PPAR?/RXR activity and improved mitochondrial function. In summary, inhibition of miR-21 is a potential therapeutic strategy for chronic kidney diseases including Alport nephropathy.

Posted by Nicola Brunetti-Pierri

Gigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation

Posted by & filed under Part 18: HORMONES.

A new pediatric disorder (named X-linked acrogigantism [X-LAG]) caused by an Xq26.3 genomic duplication and presenting with early-onset gigantism due to an excess of growth hormone has been described in the Dec 2014 issue of the New England Journal of Medicine. Of the four genes included in the Xq26.3 interval, GPR101, which encodes a G-protein-coupled receptor, was overexpressed in patients’ pituitary lesions and a recurrent mutation in GPR101 has been found in some adults with acromegaly. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone-producing cells.

Posted by Nicola Brunetti-Pierri




Oxytocin restores social behavior in the Cntnap2 mouse model of autism

Posted by & filed under Part 28: NEUROGENETICS.

Mutations in contactin-associated protein-like 2 (CNTNAP2) cause cortical dysplasia and focal epilepsy syndrome. The knockout of the mouse homolog displays many features of the human disorder. The group of Dr. Geschwind performed an in vivo screen for drugs that improve the abnormal social behavior of Cntnap2 mutant mice and found that acute administration of the neuropeptide oxytocin improved social deficits. Mutant mice were found to have a decreased number of oxytocin immunoreactive neurons in the paraventricular nucleus (PVN) of the hypothalamus and an overall decrease in brain oxytocin levels. Administration of a selective melanocortin receptor 4 agonist, which causes endogenous oxytocin release, also acutely rescued the social deficits, an effect blocked by an oxytocin antagonist. Moreover, they showed that chronic early postnatal treatment with oxytocin led to more lasting behavioral recovery and restored oxytocin immunoreactivity in the PVN. In summary, this study indicates  a dysregulation of oxytocin system in Cntnap2 knockout mice that can be treated pharmacologically.

Posted by Nicola Brunetti-Pierri

SS-31 and cardiolipin oxidative stress

Posted by & filed under Part 10: DISORDERS OF MITOCHONDRIAL FUNCTION, _.

We are increasingly aware of the role that oxidative stress plays in cellular pathophysiology. Cardiolipin, a phospholipid abundant in the inner mitochondrial  membrane, has been shown to be particularly susceptible to oxidative stress and peroxidation. This is particularly relevant due to the role that cardiolipin plays in cytochrome c activity.

A recent antioxidant compound, SS-31 (D-Arg-dimethylTyr-Lys-Phe-NH2 ), was shown to selectively bind to cardiolipin and inhibit cytochrome c peroxidase activity. SS-31 further was shown to restore cytochrome c reduction and mitochondrial oxygen utilization (Birk et al, Br J Pharmacol. 2014 Apr;171(8):2017-28).

Thus, SS-31 may represent a novel class antioxidants with cardiolipin as its’ target.

Hilary Vernon, MD PhD

Positive newborn screens for C5OH

Posted by & filed under Newborn screening, Part 09: ORGANIC ACIDS.

There is much debate as to the clinical significance of 3-methylcrotonyl-CoA carboxylase deficiency (3MCC deficiency). In thinking about this issue, I recently read a paper by Arnold et al, (Mol Genet Metab. 2012 Aug;106(4):439-41)  that describes their retrospective analysis of 35 cases of 3-MCC deficiency identified by newborn screening and confirmed by enzyme and/or molecular analysis.

One of the most interesting findings of this paper is that they found was a significant inverse correlation between C5OH level and residual enzyme activity. However, there was not a relationship between clinical symptoms and residual enzyme activity, even with enzyme activities ranging from 0.2% of normal to 58% of normal. This lends weight to the idea that 3MCC deficiency may represent a susceptibility factor for metabolic decompensation during illness, but may not be, in and of itself, enough to cause clinical disease.

Hilary Vernon, MD PhD