Posts By: Hilary Vernon

Incidential findings in exome sequencing

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As the incidence of clinical whole exome testing increases, it has become very important to discuss the possibility of unrelated, incidential findings with patients and their families. Dorscher et al(AJHG, 2013 (93) 631-640) just published the rate of incidential, actionable findings in 114 genes (which includes the ACMG recommended panel of 56 actionable genes) in 1000 […]

X-linked Cobalamin Disorder

Posted by & filed under New IEM, Part 09: ORGANIC ACIDS.

Ye et al (AJHG (2013) 93, 506-514) described a new X-linked disorder of cobalamin processing caused by transcriptional dysregulation of MMACHC (cblC, combined methylmalonic acidema and homocysteinemia). This disorder is named cblX and is caused by mutations in HCFC1. HCFC1 is a global transcriptional regulator and in addition to the biochemical phenotype, these patients also have significant neurologic consequences […]

FBXL4: A new gene implicated in mtDNA depletion

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Bonnen et al.,  in AJHG 2013 (93), 471-481 reported a new gene associated with an autosomal recessive disorder of mtDNA depeletion. This gene, FBLX4 was found through whole exome sequencing in a consanguinious family with multiple affected individuals.  Gai et al., also published an association of this gene with mitochondrial disease in the same edition of […]

Energy Deficiency and GSD III

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Muscle weakness in Glycogen Storage Disease type III (debranching disease) is thought to be due to overall muscle wasting. However, Preisler N., et al (Mol Genet Metab. 2013 May;109(1):14-20) recently demonstrated that insufficient muscle glycogenolytic capacity, in combination with liver involvement, contributes significantly to muscle fatigue. This is an interesting finding, in light of the fact that rhabdomyolysis […]

Dimethylarginine and eNOS mitochondrial redistribution

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Asymmetric dimethylarginine is an inhibitor of endothelial nitric-oxide synthase by competing with l-arginine. In 2008, Sud et al showed that that asymmetric dimethylarginine  induces translocation of endothelial nitric-oxide synthase to mitochondria via a  protein nitration dependent mechanism, resulting in potential mitochondrial dysfunction (Sud N, Am. J. Physiol. Cell Physiol. 294, C1407–1418). In a more recent article (Rafikov et al. J […]

Genetic analysis in great apes

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Vuch et al (Genet Mol Res. 2013 May 21;12(2):1731-9) published a study in which they attempted to infer a specific genetic abnormality (Beta thalassemia) based on dysmorphic skeletons of two ape skeletons of closely related but different species. They extracted tooth DNA from each of the skeletons and sequenced the beta globin locus. The beta […]

ATP synthase

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Complex V of the respiratory chain, or ATP synthase, uses the energy created by the proton electrochemical gradient across the inner mitochondrial membrane to phosphorylate ADP to ATP. It consists of 2 functional domains F1 and Fo connected by a stalk domain. Complex V abnormalities make up the smallest percentage of known disorders of mitochondrial respiratory […]

Bowel dysmotility and mitochondrial disease

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Kapur et al. (Am J Surg Path 2011 May;35(5):714-22) described the gastrointestinal neuromuscular pathology of several patients with POLG related mitochondrial disease and gastrointestinal dysmotility. The findings include unusual eosinophilic cytoplasmic granules corresponding to abnormal mitochondrial in parts of the enteric ganglia. Similar pathological findings were previously reported in another mitochondrial disease associated with gastrointestinal dysmotility, MNGIE. In our patient cohort with […]

Mutations in SERAC1 cause MEGDEL

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Wortman et al. (Nature Genetics, volume 44 (7), 797-802, 2012) recently published their discovery that mutations in SERAC1, a gene responsible for phosphatidylglycerol remodeling, are causative for MEGDEL (3-methylglutaconic aciduria with sensori-neural deafness, encephalopathy, and Leigh-like syndrome) syndrome. This disorder shows striking similarities to another disorder of phospholipid remodeling with 3-methylglutaconic aciduria and prominent mitochondrial dysfunction: Barth […]

Propionic acidemia and hearing loss

Posted by & filed under Part 09: ORGANIC ACIDS.

An individual with Propionic Acidemia in his third decade of life who is cared for in our institution recently developed hearing loss. The patient’s mother  brought to our attention that on one of the family support group websites for Propionic Acidemia she noticed another affected adult wearing hearing aids. This was a complication I had not previously […]