Posts By: Hilary Vernon

Mitochondrial metabolism and the circadian clock

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

Biochemical consequences in primary inborn errors of metabolism are often clear and predictable (i.e. elevated plasma phenylalanine in phenylalanine hydroxylase deficiency). However, potential biochemical consequences of genetic aberrations that do not have an obvious connection to metabolic pathways are much more difficult to understand. Kohsaka et al. (PLOS One, 2014 9(11): 1-16) described cardiac mitochondrial abnormalities in a mouse model with cardiac targeted disruption of the circadian clock […]

Potential therapy for MTO1 abnormalities

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

Mitochondrial tRNA modification abnormalities are a recently recognized pathologic mechanism leading to defects in oxidative phosphorylation. Genes involved in these modifications include GTPBP3, and MTO1. Tischner et al (Hum. Mol. Genet. (2015) 24 (8):2247-2266.doi: 10.1093/hmg/ddu743) recently described experiments with a mouse model for MTO1 deficiency, in which implementation of a ketogenic diet was found to subvert the oxidative phosphorylation defect, with […]

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 […]

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 […]

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 […]

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 […]

The gut microbiota influence blood brain barrier integrity

Posted by & filed under Part 03: GENERAL THEMES.

Braniste et al. recently reported in Science Translational Medicine (2014 Nov 19;6(263):263ra158. doi: 10.1126/scitranslmed.3009759) that the permeability of the mouse blood brain barrier (BBB) is influenced by the gut microbiome. They showed that germ-free mice, beginning in intrauterine life, displayed increased BBB permeability compared to mice of the same strain with normal gut flora. The increased BBB permeability was […]

Cornelia de Lange Syndrome and HDAC8 mutations

Posted by & filed under New IEM.

I recently saw a female patient with a clinically apparent genetic mosaic abnormality, including patchy distribution of hyperpigmentation, organ hemi-hypertrophy, and dental and skeletal abnormalities. Testing for obvious genetic causes including CDPX and Incontinentia Pigmenti were non-informative.  We sent whole exome sequencing which revealed a novel, presumed loss of function mutation in HDAC8. Loss-of-function mutations in HDAC8 were recently […]

MSUD and BCKD expression

Posted by & filed under Part 08: AMINO ACIDS, _.

During a recent literature review on maple syrup urine disease, I came across an older article from 1998 (Suryawan et al. Am J Clin Nutr. 1998;68:72–81.) in which the authors examined branch chain amino acid metabolism (BCAT and BCKD) in various tissues. They found that most of the oxidative capacity was in skeletal muscle and liver (with muscle  representing the […]

Sir Archibald Garrod: A historical perspective

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I was recently reading the 1923 second edition of Sir Archibold Garrod’s seminal work entitled “Inborn Error of Metabolism” (Archibold E Garrod, “Inborn errors of metabolism” Oxford university press, London England 2nd edition, 1923) for a review article I am working on, and came across the following passage: “regards (to) the chemical composition of the tissues […]