New Syndrome of GNB5 Deficiency

Posted by & filed under New IEM.

Lodder et al (AJHG 2016 Aug 10 [epub ahead of print] just reported a new genetic syndrome caused by defects in the gene GNB5. Clinical features of this condition include: developmental delay,  hypotonia, gastroesophageal reflux, retinal abnormalities, seizures and cardiac sinus-node dysfunction. Clinical expression of this disease is variable, and there appears to be some genotype-phenotype correlation, with loss of function alleles leading to a more severe phenotype. GNB5 encodes for a G protein beta subunit, and participates in inhibitory G protein signaling, and disruption of this gene likely has widespread effects on downstream cellular signaling.

This is an important condition to consider in patients with sinus node dysfunction and multi-system abnormalities, since sinus node dysfunction os relatively uncommon in children.

Hilary Vernon, MD PhD


New disorder of mitochondrial tRNA processing

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

Metodiev and colleagues (AJHG, 98(5), p993–1000, 5 May 2016 ) recently reported a new mitochondrial disorder of mt-tRNA processing. Pathogenic variants were found in in TRMT10C in  2 unrelated probands via whole exome sequencing protein. Clinical features of the probands included neonatal lactic acidosis, hypotonia, feeding difficulties, deafness, and early death from respiratory failure.

TRMT10C encodes  mitochondrial RNase P (MRPP1). MRPP1, MRPP2 and MRPP3 form the mitochondrial ribonuclease P complex, which is responsible for cleaving the 5? ends of mt-tRNAs from polycistronic precursor transcripts. Functional analysis form proband fibroblasts shows increased mt-tRNA precursors, confirming dysfunctional tRNA processing.

The clinical presentation of these two probands is very reminiscent of common mitochondrial disorders, and my first inclination in making a genetic diagnosis for similarly presenting patients would likely be to send mtDNA and a limited panel of known mitochondrial genes. With this recent publication, I am once again reminded of the diagnostic limitations of using panels of known mitochondrial genes to diagnosing patients with suspected mitochondrial disease.

Hilary Vernon, MD PhD

Whole Exome Sequencing in Inborn errors of metabolism

Posted by & filed under Exome sequencing, Part 06: DIAGNOSTIC APPROACHES.

Therapies are becoming increasingly avaible for inborn errors of metabolism making diagnosis of these disorders particularly improtant.

The New England Journal of Medicine recently published a study on whole-exome sequencing in 41 patients resulting in a diagnosis in 28 of them (68%) and a targeted intervention in 18 of them (44%).

The relatively high diagnostic yield found in this study may stem from the inclusion criterion of a metabolic  phenotype, defined as one or more of the following: a pattern of abnormal metabolites in urine, blood, or cerebrospinal fluid; abnormal results on functional studies at a biochemical or cellular level (e.g., a deficiency in the mitochondrial-respiratory-chain complex); or abnormalities on clinical history (e.g., developmental or cognitive regression), physical examination (e.g., organomegaly), neuroimaging or physiological analysis (e.g., leukodystrophy), or pathological analysis (e.g., storage vacuoles) suggestive of a neurometabolic disorder.

Moreover, the study led to the identification of 11 candidate genes newly implicated in neurometabolic diseases.


Posted by Nicola Brunetti-Pierri

mtDNA variants and LHON

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

While several different mtDNA variants are known to be associated with Leber’s hereditary optic neuropathy (LHON), penetrance is not 100%, and many of the factors contributing to increased penetrance have not been solved.

One theory is that additive mitochondrial dysfunction caused by multiple LHON associated mtDNA variants could contribute to increased severity and/or penetrance of LHON. However, a recent report by Cruz-Bermudez et al (PLOSone 2016 Jan 19;11(1):e0146816.) offers some evidence against this.

In their paper, this group describes the functional and clinical consequences of an mtDNA molecule with three LHON-associated pathogenic variants (m.11778G>A, m.14484T>C, m.11253T>C) . Comparison of cell lines harboring all 3 variants versus only one of the variants revealed no differences in mitochondrial function. In addition, the ophthalmological characteristics found in the patient harboring all three variants were found to be similar to patients harboring only a  single mtDNA LHON associated pathogenic variant.

-Hilary Vernon, MD PhD

Cell programming?

Posted by & filed under Part 03: GENERAL THEMES, Tools.

Cells respond to the environment and perform their different functions via computational operations performed by DNA-encoded circuits that process sensory information. More specifically, these operations are performed by networks of regulatory proteins that integrate signals and control the timing of gene expression. Cells can be programmed using synthetic genetic circuits to generate a desired operation.

Nielsen et al. used the hardware description language Verilog to develop Cello, a tool that enables a user to describe a circuit function. Cello ( can use information provided as algorithms that parse the Verilog text in order to automatically design a DNA sequence encoding the desired circuit.

In brief, the user can write Verilog code that is automatically transformed into a DNA sequence. The authors used Cello to design 60 circuits for E. Coli (880 kbp of DNA), for which each DNA sequence was built as predicted by the software. Across all circuits 92% of the output states functioned as predicted.

This work constitutes a hardware description language for programming living cells. These findings bear great potential (but also great risks/dangers) for biotechnology and even for medicine. Careful monitoring and guidelines with regards to advancement of this field of science are needed.

Genetic circuit design automation. Nielsen AA, Der BS, Shin J, Vaidyanathan P, Paralanov V, Strychalski EA, Ross D, Densmore D, Voigt CA. Science. 2016 Apr 1;352(6281):aac7341. PMID: 27034378

Posted by Yannis Trakadis, MD

Tools for IEM patients: Metabolic Diet App Suite

Posted by & filed under Part 03: GENERAL THEMES.

Ho et al (Molecular Genetics and Metabolism, 2016, 17: 322-327) introduced an online tool for both mobile devices and desktop computers that allows individuals with one of 15 different IEMs to plan and record meals based on individual recommendations. This app also has links to other line resources.

The app is freely available at This is an excellent resource for patients to aid in the optimization of difficult to manage dietary-controlled conditions.

Hilary Vernon, MD PhD

Autism-like behaviours in transgenic monkeys overexpressing MeCP2

Posted by & filed under Part 28: NEUROGENETICS.

MECP2 gene is mutated in Rett syndrome and MECP2 duplication is responsible for a severe developmental disorder with autistic phenotypes. A recent work published in Nature reports the generation of MECP2 transgenic monkeys. The transgenic cynomolgus monkeys (Macaca fascicularis) expressing human MeCP2 in the brain exhibit autism-like behaviours and show germline transmission of the transgene. They showed higher frequency of repetitive circular locomotion and increased stress responses. The transgenic monkeys showed less interaction with wild-type monkeys within the same group.

Posted by Nicola Brunetti-Pierri

HSCT and genetic conditions

Posted by & filed under Treatment.

Hematopoietic stem cell transplantation (HSCT) with matched unrelated donors can be used in different non-malignant genetic diseases. Abdel-Azim et al. report the outcomes of 15 patients with non-malignant genetic diseases who received HSCT from 2006 to 2014.

Fifteen patients were enrolled during the study period: 26.7% female (n = 4), 33.3% Hispanic (n = 5), 40% African American (n = 6), 26.7% Caucasian (n = 4).

Median patient age at transplant was 7 (0.8–17.6) years. Diagnoses included HLH (n = 2), CD40 ligand deficiency [CD40-L] (n = 2), congenital dyserythropoietic anemia [CDA] type I (n = 1), CDA type II (n = 1), ALD (n = 1), sickle cell diseases [SCD] (N = 7), and b-thalassemia (n = 1, class II).

At a median follow-up of 2 (0.2-5.4) years, the overall survival (OS) was 93.3% (95% CI: 0.61-0.99) and disease-free survival (DFS) was 73.3% (95% CI: 0.44-0.89).

Alemtuzumab was associated with durable donor engraftment and relatively low rates of regimen related toxicity.

Unrelated donor hematopoietic stem cell transplantation for the treatment of non-malignant genetic diseases: An alemtuzumab based regimen is associated with cure of clinical disease; earlier clearance of alemtuzumab may be associated with graft rejection. Abdel-Azim H, Mahadeo KM, Zhao Q, Khazal S, Kohn DB, Crooks GM, Shah AJ, Kapoor N. Am J Hematol. 2015 Nov;90(11):1021-6. PMID: 26242764


Posted by Yannis Trakadis, MD


Hypoxia as a therapy for mitochondrial disease

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

Jain et al. performed a genome-wide, Cas9-mediated screen using the human leukemic suspension cell line, K562, to identify factors that are protective during mitochondrial respiratory chain (RC) inhibition.

Hypoxia response, an endogenous program evolved to adapt to limiting oxygen availability, was a very interesting finding.

Genetic or small molecule activation of the hypoxia response appears to be protective against mitochondrial toxicity in cultured cells and zebrafish models. Marked improvement was noted in survival, body weight and temperature, behavior, neuropathology and disease biomarkers in a genetic mouse model of Leigh syndrome.

The preclinical studies described by Jain et al. support that hypoxic gas mixtures may be useful in the management of mitochondrial disorders. Hypoxia activates an adaptive response that allows mammals to cope with limiting oxygen levels, thus decreasing the reliance on mitochondrial oxidative metabolism. Given, in mitochondrial disease the hypoxia signal is not present, this adaptive response is not necessarily activated.

This study raises the possibility of hypoxic gas mixtures as a potential therapeutic approach for patients with mitochondrial disease. Interestingly, the current study has utilized a chronic 11% inspired oxygen and healthy humans can reportedly acclimate to high altitudes where oxygen availability is comparable to that used in the experiments.

Before the chronic hypoxia strategy described here can be evaluated in the clinical setting, additional pre-clinical studies are needed to establish its safety, efficacy and generalizability.

Hypoxia as a therapy for mitochondrial disease. Jain IH, Zazzeron L, Goli R, Alexa K, Schatzman-Bone S, Dhillon H, Goldberger O, Peng J, Shalem O, Sanjana NE, Zhang F, Goessling W, Zapol WM, Mootha VK. Science. 2016 Feb 25. pii: aad9642. PMID: 26917594

posted by Yannis Trakadis, MD

Adipose transplant for MSUD

Posted by & filed under Part 08: AMINO ACIDS.

In an article from a couple of years ago, Zimmerman et al (Mol Genet Metab. 2013 Aug;109(4):345-53) discuss evidence for improvement of biochemical measures with adipose transplant in 2 mouse models of maple syrup urine disease (MSUD).

This brings up the very interesting question about which soft tissues provide adequate enzymatic activity for therapeutic replacement potential. This could be either an adjunctive therapy to improve general control in a condition such as MSUD, or potentially a long term single therapy depending on the restoration of metabolic control.

Hilary Vernon, MD PhD