Meta-analysis: heritability of different traits

Posted by & filed under Part 03: GENERAL THEMES.

Polderman et al. recently published in Nature Genetics a meta-analysis of twin correlations and reported variance components for 17,804 traits. In total, 2,748 publications including 14,558,903 partly dependent twin pairs, virtually all published twin studies of complex traits, were taken into consideration.

For 69% of the traits studied, the observed twin correlations are consistent with a simple and parsimonious model where twin resemblance is solely due to additive genetic variation. In the context of the recent advancements of genomic technologies (e.g. exome/genome sequencing), this study and the MaTCH webtool which can be used to visualize its results can be particularly useful for future gene-maping endeavors and for better understanding the pathophysiology of complex traits.

Meta-analysis of the heritability of human traits based on fifty years of twin studies. Polderman TJ, Benyamin B, de Leeuw CA, Sullivan PF, van Bochoven A, Visscher PM, Posthuma D. Nat Genet. 2015 Jul;47(7):702-9. doi: 10.1038/ng.3285. Epub 2015 May 18. PMID: 25985137

Posted by Yannis Trakadis, MD

LONP1 mutations in CODAS Syndrome

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

Dikoglu et al (AJMG 2015 Volume 167,  Issue 7pages 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 of mitochondrial function.

Hilary Vernon, MD PhD

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 repression ureter mesenchyme and smooth muscle cells.

Hilary Vernon, MD PhD

Recurrent mutations in NF1 and RASopathy genes melanomas

Posted by & filed under Part 04: CANCER.

A whole-exome sequencing (WES) study on 213 melanomas found that NF1, encoding a negative regulator of RAS mutated in Neurofibromatosis type 1, is the third most frequently mutated gene in melanoma, after BRAF and NRAS. Inactivating NF1 mutations were present in 46% of melanomas expressing wild-type BRAF and RAS, occurred in older patients and showed a distinct pattern of co-mutation with other RASopathy genes, particularly RASA2.

Posted by Nicola Brunetti-Pierri

SAM in creatine transporter deficiency

Posted by & filed under Treatment.

Jaggumantri et al. recently published an open-label observational study to evaluate the effect of adjunct S-adenosyl methionine (SAM) in Creatine transporter (SLC6A8) deficiency. This X-linked condition is characterized by cerebral creatine deficiency, behavioral problems, seizures, hypotonia, and intellectual disability. Only some patients respond to high-dose oral creatine, glycine, and L-arginine supplementation.

SAM (50/mg/kg) was used in two male patients an effort to boost the intracerebral creatine synthesis. Issues with sleep and behavior were noted on this dosage in both patients. One of the two patients was lost in follow-up. The dose was progressively adjusted to 17 mg/kg/day in the other patient, which was well tolerated and led to significant improvement in speech/language skills, muscle mass, as well as, in activities related to communication and decision making described by the family.

This study raises the possibility that SAM may be used as an adjunctive therapy for patients with creatine transporter deficiency but further studies with increased sample size are needed to explore the significance of this finding.

Treatment of Creatine Transporter (SLC6A8) Deficiency With Oral S-Adenosyl methionine as Adjunct to L-arginine, Glycine, and Creatine Supplements. Jaggumantri S, Dunbar M, Edgar V, Mignone C, Newlove T, Elango R, Collet JP, Sargent M, Stockler-Ipsiroglu S, van Karnebeek CD. Pediatr Neurol. 2015 May 16. pii: S0887-8994(15)00231-3. doi: 10.1016/j.pediatrneurol.2015.05.006. PMID: 26205312

Posted by Yannis Trakadis, MD

Engineering the gut microbiota to treat hyperammonemia

Posted by & filed under Part 08: AMINO ACIDS.

Gut microbiota can be altered to ameliorate or prevent disease states. In the intestine, bacterial urease converts host-derived urea to ammonia and carbon dioxide, contributing to hyperammonemia-associated neurotoxicity and encephalopathy in patients with liver disease.

In their JCI paper, Shen and colleagues engineered murine gut microbiota to reduce urease activity. Animals were depleted of their preexisting gut microbiota and then inoculated with altered Schaedler flora (ASF), a defined consortium of 8 bacteria with minimal urease gene content. This protocol resulted in establishment of a persistent new community that promoted a long-term reduction in fecal urease activity and ammonia production. Moreover, in a murine model of hepatic injury, ASF transplantation was associated with decreased morbidity and mortality. These results provide proof of concept that inoculation of a prepared host with a defined gut microbiota can lead to durable metabolic changes with therapeutic utility. Besides liver diseases, urea cycle disorders are also targets for this therapeutic approach.

Posted by Nicola Brunetti-Pierri

Is BRIEF sufficient to monitor executive function in PKU?

Posted by & filed under Part 08: AMINO ACIDS.

Liemburg et al. (2015) explored if the Behavior Rating Inventory of Executive Function (BRIEF) instrument is sufficient to monitor for Executive Function (EF) deficits in patients with PKU.

55 adult PKU patients (mean age 28.3 ± 6.2 years) filled out the BRIEF-A questionnaire and performed computerized tasks measuring executive functions (inhibition, cognitive flexibility, and working memory). The outcome of the BRIEF-A questionnaire was compared with the neurocognitive outcome as measured by three tasks from the Amsterdam Neuropsychological Tasks (ANT).

BRIEF-A results: 42% of the PKU patients scored in the borderline/clinical range; 11% scored >1 SD above the normative mean (higher being poorer score).

ANT results: 34-36% of patients showed deficits in inhibitory control; 31-24% showed deficits in cognitive flexibility, as compared to the general Dutch population.

No significant correlations between the two methods were found, which was confirmed with the Bland-Altman approach where no agreement between the two methods was observed.

The study concludes that patients reporting EF problems in daily life are not necessarily those that present with core EF deficits and that BRIEF-A is not a sufficient way to monitor EF in adult PKU patients.

Is BRIEF a useful instrument in day to day care of patients with phenylketonuria? Liemburg GB, Jahja R, van Spronsen FJ, de Sonneville LM, van der Meere JJ, Bosch AM, Hollak CE, Rubio-Gozalbo ME, Brouwers MC, Hofstede FC, de Vries MC, Janssen MC, van der Ploeg AT, Langendonk JG, Huijbregts SC. Mol Genet Metab. 2015 Mar;114(3):425-30. PMID: 25541101

Posted by Yannis Trakadis, MD

MAOA & COMT polymorphisms modifying psychiatric symptoms in Huntington’s

Posted by & filed under Part 28: NEUROGENETICS.

A cohort of Danish CAG repeat-expansion carriers in HTT gene, diagnosed with Huntington’s disease (HD), was recently published by Vinther-Jensen et al. (2015). This study focused on symptom complexes and searched for modifiers of cognitive impairment and psychiatric symptoms. Based on the results of Vinther-Jensen et al., cognitive impairment and psychiatric symptoms in HD are modified by polymorphisms in the MAOA and COMT genes and by the 4p16.3 B haplotype. Dopamine is thought to be implicated in cognition, behavioral and motor disturbances and its imbalance has previously been shown in HD. The findings of this study provide further evidence for dopamine’s role in HD and point towards more personalized treatment modalities of HD in the future.

Posted by Yannis Trakadis, MD

Psychiatric and cognitive symptoms in Huntington’s disease are modified by polymorphisms in catecholamine regulating enzyme genes T Vinther-Jensen, TT Nielsen, E Budtz-Jørgensen, IU Larsen, MM Hansen, L Hasholt, LE Hjermind, JE Nielsen and A Nørremølle Accepted manuscript online: 17 JUN 2015 01:33AM EST | DOI: 10.1111/cge.12628


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 in particular for targeted studies due to reports of  individuals with myoclonic-astatic epilepsy and chromosome deletions in the region covering this gene, as well as functional information about  GAT-1. Two truncations and four missense alterations in SLC6A1 were uncovered by targeted sequencing individuals with myoclonic-atonic seizures (MAE). Hilary Vernon, MD PhD

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 of clinical severity, and an apparently moderate impairment of fatty acid oxidation compared to the severity clinical features. Therefore, the authors postulate that the impairment in amino acid oxidation contributes significantly to the phenotype.

This disorder should be suspected in an individual with the above clinical features and urine organic acid findings of increased ethylmalonate and 2-methyl-2,3 dihydroxybutyrate.

Hilary Vernon, MD PhD