Posts By: Hilary Vernon

iINDs and inborn errors of metabolism

Posted by & filed under Treatment.

In the recent edition of Molecular Genetics and Metabolism, P. Dickson and J. Tolar discuss the potential of individual investigational new drug applications (iINDs) for N-of-One therapeutic trials of experimental therapies in inborn errors of metabolism (Mol Gen Metab 116 (2015):1-3). They discuss “pros”: faster bench to bedside translation, treating life-threatening conditions with no other therapeutic options, and “cons”: […]

ACVR1 R206H receptor mutation: a “gain of function” mutation cause of fibrodysplasia ossificans progressiva

Posted by & filed under Part 22: CONNECTIVE TISSUE.

Hatsell et al (Sci Transl Med. 2015 Sep 2;7(303):303ra137. doi: 10.1126/scitranslmed.aac4358) recently published very exciting work on the mechanism of the common ACVR1 gene mutation underlying fibrodysplasia ossificans progressive (FOP). This mutation confers the ability of the BMP 1 receptor ACVR1 to respond to  the inflammatory response ligand Activin A, and induce bone formation. This mechanism explains […]

Heimler Syndrome: a mild peroxisome biogenesis disorder

Posted by & filed under Part 15: PEROXISOMES.

Peroxisome biogenesis disorders are generally considered to be severe multisystem disorders, often with a progressive component. However, Ratbi et al, in the recent edition of American Journal of Human Genetics (2015 (97): 535-545) report that Heimler Syndrome, a disorder of hearing loss, abnormal dentition and nails, with or without retinitis pigmentosa, is due to hypomorphic […]

Post-zygotic Point Mutations

Posted by & filed under Part 06: DIAGNOSTIC APPROACHES.

My general practice in counseling families with a  child who has a suspected “de novo” dominant disorder is to estimate an approximate 5% recurrence risk for their future children based on potential gonadal mosaicism in the parents. However, a recent paper by Acuna-Hidalgo et al (AJHG, Volume 97, Issue 1, p67–74, 2 July 2015) presented work in which they found […]

Propofol use in methylmalonic acidemia

Posted by & filed under Part 09: ORGANIC ACIDS.

Our department’s general practice when advising on patients with organic acidemias who require surgery is to avoid the use of propofol. This practice was developed after a patient with methylmalonic acidemia (MMA) developed pancreatitis after a surgical procedure during which profofol was administered. However a recent review of the anesthesia administration in a cohort of 28 patients […]

LONP1 mutations in CODAS Syndrome

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

Dikoglu et al (AJMG 2015 Volume 167,  Issue 7, pages 1501–1509) report the identification of the gene responsible for CODAS syndrome, an ultra- rare syndrome named for its’ cardinal features: Cerebral, ocular, dental, auricular, and skeletal anomalies. The responsible gene, LONP1, likely plays a role in protein turnover within the mitochondrial matrix. Thus, this represents another unique mechanism for a primary disorder […]

Congenital anomalies of the kidneys and urinary tract and TBX18

Posted by & filed under Part 24: KIDNEY.

Until a recent publication by Vivante et al, in the American Journal of Human genetics (July 2015, available on-line, in press), genes responsible for Congenital anomalies of the kidneys and urinary tract (CAKUT) were elusive. They identified 4 families with dominant negative mutations in TBX18. The mechanism of pathogenicity is thought to be interference with TBX18 transcriptional […]

Variants in SLC6A1 and Doose Syndrome

Posted by & filed under Part 21: MEMBRANE TRANSPORT DISORDERS, Part 28: NEUROGENETICS.

Doose Syndrome, also known as myoclonic-astatic epilepsy, is a form of epilepsy in which the genetic etiology has been somewhat elusive. A recent study by Carvill et al (Am J Hum Genet 2015 May 7;96(5):808-15. doi: 10.1016/j.ajhg.2015.02.016) reports that pathogenic variants in GAT-1, encoded by SLC6A1, can be responsible for up to 4% of cases of myoclonic-astatic epilepsy. Carvill et al. focused on this gene […]

ECHS1 deficiency and mitochondrial disease

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

Haack et al (Annals of Clinical and Translational Neurology, 2015, 2 (5) pp. 492-509) recently reported a disorder of encephalopathy, deafness, optic atrophy, and cardiomyopathy caused by mutations in short-chain enoyl-CoA hydratase  (ECHS1). This mitochondrial matrix enzyme functions in the oxidation of fatty acids and some amino acids (particularly valine). Patients present with a wide range […]

Risk of tumors in Bohring-Opitz Syndrome

Posted by & filed under Part 04: CANCER.

Bohring-Opitz Syndrome (BOS, MIM 612990) is a rare condition characterized by dysmorphic features, failure to thrive, severe intellectual disability,  nevus flammeus and myopia. It can be caused by heterozygous mutations in ASXL1, a gene involved in the regulation of Hox genes. Russel et al. (AJMG, 2015, Apr 29. doi: 10.1002/ajmg.a.37131. [Epub ahead of print]) just published clinical management […]