Nuclear Pyruvate Dehydrogenase Complex Generates Acetyl-CoA for Histone Acetylation

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

The mitochondrial pyruvate dehydrogenase complex (PDC) is a key enzyme in metabolism but also has a newly recognized functional role in the nucleus of mammalian cells.  Sutendra and colleagues have discovered that PDC translocates from the mitochondria to the nucleus  in a cell-cycle-dependent manner and in response to serum, epidermal growth factor, or mitochondrial stress.  Inhibition of nuclear PDC decreased acetylation of specific lysine residues on histones important for G1-S phase progression and expression of S phase markers.

In summary, DNA transcription, replication, and repair are regulated by histone acetylation, a process that requires the generation of acetyl-coenzyme A (CoA) that is provided by dynamic translocation of mitochondrial PDC to the nucleus.

Posted by Nicola Brunetti-Pierri, MD

A framework for the interpretation of de novo mutation in human disease

Posted by & filed under Exome sequencing, Part 28: NEUROGENETICS.

Samocha et al. A framework for the interpretation of de novo mutation in human disease. Nat Genet. 2014 Aug 3.


Samocha et al describe a sophisticated statistical model designed to better evaluate data derived from mass exome sequencing studies, specifically with respect to the significance of excesses of de novo mutations in diseases with significant locus heterogeneity such as autism spectrum disorders. They derive the predicted number of de novo mutations for a given gene by combining several parametres such as gene length, sequence context, depth of coverage during sequencing, and regional divergence around the gene between humans and macaques. This allows a comparison between expected and observed de novo mutations for groups of affected and unaffected individuals, which yields a more powerful analysis than direct comparison between groups. Likewise, the model allows the identification of groups of genes that, in normal subjects, exhibit less de novo functional variation than expected, implying a selective pressure against loss of function (“constrained genes”).

The authors then apply this framework to the study of autism spectrum disorders. They find that there is no global excess of de novo functional mutation in ASD subjects, but rather an excess of genes with more than one de novo functional mutation, as well as an excess of de novo mutations in “constrained” genes,  as well as in genes that are the targets of FMRP. Surprisingly, these observations were not true of ASD subjects with IQ above 100, suggesting that the genetic underpinnings of ASD are different in this subgroup.

The analysis of exome data for multifactorial diseases exhibiting significant locus heterogeneity requires different, and more complex, bioinformatic tools than for monogenic disorders. This study is an example of the value of developing and perfecting them.

HMGCR is a genetic modifier for risk, age of onset and MCI conversion to Alzheimer’s disease

Posted by & filed under Part 12: LIPIDS, Part 28: NEUROGENETICS.

Leduc V et al. HMGCR is a genetic modifier for risk, age of onset and MCI conversion to Alzheimer’s disease in a three cohorts study. Mol Psychiatry. 2014 Jul 15

Leduc et al report a new genetic modulator of the risk for sporadic Alzheimer’s disease (AD) occurrence, as well as the risk of conversion from mild cognitive impairment to full-blown AD. HMGCR encodes 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme in cholesterol synthesis and the molecular target of statins. The authors find that G negative (AA) status in the HMGCR rs3846662, an intronic polymorphism involved in exon 13 skipping, is protective with respect to the risk of acquiring AD, the age of onset, and the risk of conversion of mild cognitive impairment to AD, specifically in women.

The methodology is interesting (particularly for those of us with a Montreal connection) in that the authors first identified this association in the more homogeneous French Canadian population, and then found that it could be generalised to two different mixed North American populations.
This study joins the body of evidence suggesting that lipid and cholesterol metabolism is crucial to the pathophysiology of Alzheimer’s disease. However, whether the protective effect identified is mediated by alterations in cerebral cholesterol metabolism directly or by better vascular health remains to be determined.

10-year follow-up study of ERT for MPS VI patients

Posted by & filed under Part 16: LYSOSOMAL DISORDERS.

Giugliani R. Natural history and galsulfase treatment in mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome)-10-year follow-up of patients who previously participated in an MPS VI survey study. Am J Med Genet A. 2014 Aug;164(8):1953-64.


Giugliani et el evaluate the long-term effects of enzyme replacement therapy in Maroteaux-Lamy syndrome (MPS VI) by conducting a resurvey of the 121 patients first evaluated in a cross-sectional study in 2001-2002. With a ten-year follow-up period, this is the longest longitudinal study of treated MPS VI patients to be performed to date. They were able to obtain information on survival for almost all patients (117), but clinical assessments and medical histories for less than half (59). The authors find that the ERT-treated group had longer survival, improved pulmonary function and endurance, and stabilised cardiac function.
Although the absence of randomisation and the small size of the ERT-naive group (14 patients in total, with medical histories and clinical assessments available for only 4) may introduce a selection bias, the study offers strong evidence for the long-term benefits of ERT for patients with Maroteaux-Lamy syndrome. It is possible that even better outcomes could be achieved with earlier initiation of therapy.


New monogenic early-onset polyautoimmunity syndrome caused by activating mutations in STAT3

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

Flanagan SE et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.Nat Genet. 2014 Aug;46(8):812-4.

Monogenic autoimmunity syndromes are a rare cause of very early-onset multiple autoimmune manifestations. Flanagan et al report a new monogenic early-onset polyautoimmunity syndrome caused by activating STAT3 mutations. They initially used exome sequencing to identify an activating de novo germline STAT3 mutation in a patient presenting with extremely early-onset type 1 diabetes mellitus (2 weeks), hypothyroidism (3 years), and celiac disease (17 months); they then went on to identify four more patients with de novo STAT3 mutations by screening a cohort of patients with more than two early-onset autoimmune disorders and 39 patients with unexplained  onset of permanent diabetes mellitus before 6 months. Other manifestations included autoimmune enteropathy and interstitial lung disease, juvenile-onset arthritis, hypothyroidism, eczema, and short stature.

The STAT (signal transducer and activator of transcription) factors are involved in early development, cell differentiation and proliferation. Interestingly, germline inactivating STAT3 mutations are associated with hyper-IgE syndrome, and somatic activating STAT3 mutations with large granular lymphocytic leukemia and inflammatory hepatocellular adenoma. Polymorphisms in STAT3 have been reported in association with autoimmune conditions other than those described here (Crohn’s disease, psoriasis, multiple sclerosis). The authors suggest that the mechanism of pathogenicity of activating STAT3 mutations is impaired regulatory T cell development and dysregulated proliferation and activation of helper T cells type 17.

Exome sequencing technology has the potential to expand our understanding of autoimmunity, both by identifying causes of rare monogenic disorders and by improving our understanding of the molecular pathophysiology of common diseases.

Posted by Alina Levtova, MD

VARS2 and TARS2 mutations associated with mitochondrial disease

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

Increasingly, whole exome sequencing has been critical in resolving molecular causes of unknown metabolic or mitochondrial disorders. Diodato et al (Hum Mutat. 2014 Aug;35(8):983-9) used WES to identify homozygous mutations in VARS2 (Valyl tRNA synthetase)  in one patient seizures and deficiency mitochondrial respiratory chain complex I, and compound heterozygous mutations in TARS2 (threonyl-tRNA synthetase) in siblings with hypotonia, severe psychomotor delay and multiple respiratory chain defects.

The mitochondtial tRNA synthetases are an increasingly being implicated in a wide range of mitochondrial disorders and encephalopathies. However, the genes for these tRNAs are not included on most mitochondrial disease gene testing panels. Thus, whole exome sequencing is currently the most efficient way to diagnose them.

Hilary Vernon, MD PhD

False positive newborn screens for C5

Posted by & filed under Part 09: ORGANIC ACIDS.

It can be very difficult to definitively rule out some inborn errors of metabolism once an infant has screened positive, and it is helpful to understand what circumstances may contribute to false positive results. An interesting situation was reported by Boemer et al (Mol Genet Metab. 2014 Jan;111(1):52-4.), in which a pivalate derivative was used in skin emollients provided to some new mothers in Belgium. This derivative was leading to false positive C5 screens in a series of  infants, who were probably ingesting this emmolient while breastfeeding.  Stopping the distribution of this emmolient reduced the C5 false positive rate.

This case emphasizes how astute observations and simple interventions can affect the accuracy of the newborn screening process.

Hilary Vernon, MD PhD

Dietary management of older patients with classical galactosemia

Posted by & filed under Part 07: CARBOHYDRATES.

Van Calcar SC. A re-evaluation of life-long severe galactose restriction for the nutrition management of classic galactosemia. Mol Genet Metab. 2014 Jul;112(3):191-197.


Although the need for galactose restriction in infants with classic galactosemia is unquestioned, the value of very severe galactose restriction for older individuals is controversial. Van Calcar et al review current practices and make recommendations based on the available literature. They find that there is considerable heterogeneity in treatment around the world, particularly with respect to allowing minor sources of galactose from dairy (e.g. cheeses) and plant sources. The authors suggest the inclusion in the diet of fruits, vegetables, juices, legumes, and all non-fermented soy based products, as well as specific hard cheeses and the dairy-based additives, calcium and sodium caseinate. They also stress the importance of ensuring adequate calcium and vitamin D intake.

The risks and benefits of liberalising the diet for older/adult patients with galactosemia, as well as the pathophysiology and prevention of long-term complications, remain important and incompletely understood issues that require further study.


Posted by Alina Levtova, MD

Glycogen storage disease types 0, VI, and IX in the differential diagnosis of idiopathic ketotic hypoglycemia of childhood

Posted by & filed under Part 07: CARBOHYDRATES.


Brown LM et al. Evaluation of glycogen storage disease as a cause of ketotic hypoglycemia in children. J Inherit Metab Dis. 2014 Jul 3. [Epub ahead of print]

In this study, Brown et al screened a population of children with seemingly idiopathic ketotic hypoglycemia for the “milder” glycogen storage disorders type 0, VI, and IX by DNA sequencing of the relevant genes. 164 children with recurrent ketotic hypoglycemia, a normal standard endocrine and metabolic work-up, and no hepatomegaly (or at least none detected on physical exam) were studied; patients do not, however, seem to have been routinely screened for postprandial hyperlactataemia, which might have oriented the investigation towards GSD 0 directly. Twelve percent of patients were diagnosed with a glycogen storage disorder (four GSD 0, two GSD VI, 12 GSD IX alpha, one GSD IX beta, one GSD IX gamma). Although the authors themselves point out the probable existence of a significant selection bias, this study underlines the importance of considering these glycogen storage disorders in the differential diagnosis of seemingly idiopathic ketotic hypoglycemia.

Posted by Alina Levtova, MD

Genome sequencing and severe intellectual disability

Posted by & filed under _.

Severe intellectual disability occurs in 0.5% of newborns. Over the last years, using microarrays and exome sequencing has aided in the explanation of a big proportion of ID.

Gilissen et al (2014) applied whole-genome sequencing to 50 patients with severe ID (whose extensive genetic work-up, including microarray and exome sequencing, was negative) and their unaffected parents.

84 de novo SNVs affecting the coding region were identified. A statistically significant enrichment of loss-of-function mutations and an enrichment for genes previously implicated in ID-related disorders were noted. Moreover, 8 de novo CNVs were identified, including single-exon deletions,  intra-exonic deletions, and interchromosomal duplications affecting known ID genes more frequently than expected.

The authors conclude that their overall diagnostic yield in this extensively studied cohort of severe ID was  “42%, and 62% as a cumulative estimate in an unselected cohort”.

Genome sequencing identifies major causes of severe intellectual disability. Gilissen C, Hehir-Kwa JY, Thung DT, van de Vorst M, van Bon BW, Willemsen MH, Kwint M, Janssen IM, Hoischen A, Schenck A, Leach R, Klein R, Tearle R, Bo T, Pfundt R, Yntema HG, de Vries BB, Kleefstra T, Brunner HG, Vissers LE, Veltman JA. Nature. 2014 Jul 17;511(7509):344-7. doi: 10.1038/nature13394. Epub 2014 Jun 4. PMID: 24896178


Posted by Yannis Trakadis, MD