DNA methylation in mtDNA

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

I was recently reviewing evidence for epigenetic control in mitochondrial DNA and came across a nice review by Iacobazzi et al (Mol Gen Metab 2013, 110(2) 25-34). In this review, the authors describe evidence for methylation and other mechanisms for epigenetic control of mtDNA, and methodology for exploration of this. They also discuss evidence for this mechanism in human disease.

In my opinion, this is a significantly under-discussed area in inborn errors of metabolism (IEM); particularly in how downstream effects of some well-known IEMs may affect expression of mtDNA genes, and a rich area for further study.

Hilary Vernon, MD PhD

Triheptanoin and long chain fatty acid oxidation disorders

Posted by & filed under Part 12: LIPIDS.

Roe and Brunengraber recently reported outcomes in a large cohort of individuals with long chain fatty acid oxidation disorders (Molecular Genetics and Metabolism, 2015; 116(4):260-268). They compared therapy with MCT oil and low fat-high carbohydrate diet versus diet therapy+carnitine+trihepatanoin. The outcomes were quite striking: average frequency of serious clinical complications was approximately 60% with diet therapy alone compared to 10% with diet therapy+carnitine+triheptanoin.  Even more strikingly, mortality decreased from 65%  to 3.8%.

The therapy with triheptanoin and carnitine is aimed at “refilling” the anapleurotic deficit of the TCA cycle in long chain fatty acid disorders, and this reasoned approach drastically improves outcome.

Hilary Vernon, MD PhD

Organic acidurias: impact of age at onset and NBS

Posted by & filed under Newborn screening, Part 09: ORGANIC ACIDS.

The information of 567 patients with organic acidurias (OADs) from the E-IMD registry were analysed using recursive partitioning of diagnostic and therapeutic strategies, and odds ratios (OR) for health outcome parameters. Different OADs were included in this study: methylmalonic (MMA, n=164), propionic (PA, n=144), isovaleric (IVA, n=83), and type 1 glutaric aciduria (GA1, n=176).

Of all OAD patients 71 % remained asymptomatic until day 8. Patients identified by newborn screening (NBS) had a significantly lower median age of diagnosis (8 days) compared to the late onset, (LO) group, but not compared to the early onset (EO) group (where EO represents patients presenting with symptoms during, while LO after, the newborn period).

This study concluded that NBS is an effective intervention to reduce time until diagnosis especially for LO patients and to prevent irreversible cerebral damage in GA1 and MMA-Cbl-. For other OADs, the clinical benefit of NBS was less clear. Moreover, the vast diversity of therapeutic interventions made it impossible to draw conclusions about optimal treatment.

Impact of age at onset and newborn screening on outcome in organic acidurias. Heringer J, et al. E-IMD consortium. J Inherit Metab Dis. 2015 Dec 21. PMID: 26689403

Posted by Yannis Trakadis, MD

Gene therapy and Primary hyperoxaluria type 1

Posted by & filed under Treatment.

Primary hyperoxaluria type 1 (PH1) is a condition caused by a deficiency of the peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). PH1 is estimated to account for about 1% of pediatric cases of end-stage renal failure and to occur in 1:120,000 live births in Europe. It typically presents with renal colic or asymptomatic gross hematuria before the age of 5 years. Almost half of patients present with end-stage renal disease at the time of diagnosis.

Liver transplantation or combined liver/kidney transplantation are the only available therapeutic modalities to prevent disease progression. Castello et al. recently explored helper-dependent adenoviral (HDAd) vectors for liver-directed gene therapy of PH1 in AGT-deficient mice.

A significant reduction of hyperoxaluria was reported in mice injected with an HDAd encoding the AGT (under the control of a liver-specific promoter) when compared with control mice injected with saline. AGT catalyzes the reaction of glyoxylate into glycine. Ethylene glycol is a precursor of glyoxylate. A challenge of the two groups of mice with ethylene glycol showed that the mice having been treated with gene therapy showed less increase of urinary oxalate, providing further evidence that the treatment has had a significant impact.

For more information on primary hyperoxaluria, you can refer to chapter 133 of OMMBID.

Helper-dependent adenoviral vectors for liver-directed gene therapy of primary hyperoxaluria type 1. Castello R, Borzone R, D’Aria S, Annunziata P, Piccolo P, Brunetti-Pierri N. Gene Ther. 2015 Dec 24. doi: 10.1038/gt.2015.107. [Epub ahead of print] PMID: 26609667

Posted by Yannis Trakadis, MD

Beta-mannosidase gene mutations in autosomal dominant nystagmus

Posted by & filed under Part 16: LYSOSOMAL DISORDERS.

A recent study in Genetics in Medicine aiming at the identification by whole-exome sequencing of genes involved in infantile nystagmus found heterozygous missense mutations in the MANBA gene, which the encodes lysosomal beta-mannosidase. The mutations resulted in decrease of ?-mannosidase activities in the patients as well as in mutant-transfected HEK293T cells.

MANBA is expressed in the pretectal nucleus of the developing midbrain, known to be involved in oculomotor and optokinetic nystagmus. Further analysis revealed that nystagmus is present in at least 24 different lysosomal storage diseases involving the brain.

This is the first identification of MANBA mutations in patients with autosomal-dominant nystagmus, suggesting a new clinical entity.

http://www.nature.com/gim/journal/v17/n12/abs/gim201510a.html#affil-auth

 

Posted by Nicola Brunetti-Pierri

 

A syndrome of Golgi Dysfunction

Posted by & filed under New IEM.

I am quite used to thinking of only the mitochondria in terms of Mendelian Disorders of organelle dysfunction, which is my own bias because of the majority of the patients I see. However, I was very interested to read a recent article published by Schmidt et al (AJHG (2015)97, 855-861) in which they describe an inherited disease of Golgi integrity caused by mutations in the SCYL1 gene.

This is an autosomal recessive disorder characterized by recurrent liver failure, neuropathy, and cerebellar atrophy. Interestingly, the recurrent episodes of liver failure in affected patients were generally precipitated by fevers.

Hilary Vernon, MD PhD

A new gene for Optic Neuropathy

Posted by & filed under New IEM.

Optic neuropathy with or without other features is a common cause of referral to mitochondrial specialists, and can pose a diagnostic challenge. Whereas isolated optic neuropathies in and of themselves are devastating enough, those associated with broader mitochondrial diseases can herald a multi-organ progressive disorder.

Angebault et al (AJHG 2015 (97) 754-760) described a new gene for isolated and syndromic optic neuropathy: RTN4IP1. This gene encodes a mitochondrial ubiquinol oxydo-reductase, and fibroblasts from affected individuals have evidence of complex I and IV deficiencies. Affected patients have features ranging from isolated optic neuropathy to a cerebellar syndrome with intellectual disabilities. While only a few patients have been identified to date, the phenotypic spectrum will likely expand as more individuals are identified.

Hilary Vernon, MD PhD

Mutations in SLC25A26 and mitochondrial methylation defects

Posted by & filed under New IEM.

Kishita et al (AJHG 2015( 97) 761-768) just published a very interesting paper in which they describe that mutations in the mitochondrial S-adenosylmethionine (SAM) transporter SLC25A26 cause an autosomal recessive, severe mitochondrial disease. The mitochondrial functional defects are shown to be widespread and include RNA instability, translational defects, and cofactor biosynthetic defects.

This leads one to wonder about how other methylation defects leading to SAM imbalances could also lead to downstream mitochondrial defects.

Hilary Vernon, MD PhD

Defects of the mitochondrial S-adenosylmethionine transporter cause intramitochondrial methylation deficiency

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

Mutations in SLC25A26, encoding the mitochondrial S-adenosylmethionine (SAM) transporter, were identified in patients in three families though homozygosity mapping and exome sequencing. Clinical manifestations ranged from foetal hydrops to episodes of lactic acidosis and cardiopulmonary collapse in childhood with chronic progressive muscle weakness.

The authors showed that the defect of SAM import into mitochondria causes an intramitochondrial methylation deficiency, which in turn affects mitochondrial RNA stability, protein modification, mitochondrial translation, and the biosynthesis of CoQ10 and lipoic acid. This a novel and fascinating mechanism of mitochondrial disease.

Interestingly, the group found that intramitochondrial methylation was not entirely abolished, suggesting the existence of alternative mechanisms, such as other forms of methylation or recycling of methyl groups originating from imported methylated proteins. To me, this underlines the fact that intramitochondrial methylation is still incompletely explored, and implies that a better understanding of these alternative mechanisms might lead to potential treatment options for this condition.

This study also highlights the physiological importance of intramitochondrial methylation. I think it might be interesting to speculate on the role that a secondary deficiency in intramitochondrial methylation might play in the pathophysiology of remethylation disorders that result in a global deficiency of SAM (e.g. MTHFR deficiency).

Kishita Y, Pajak A, Bolar NA, et al (2015) Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26. Am J Hum Genet 97: 761-768.

Biotinidase deficiency should be considered in the differential diagnosis of myelopathy

Posted by & filed under Part 17: VITAMINS, _.

In this review, B. Wolf highlights the importance of considering biotinidase deficiency in the differential diagnosis of myelopathy. He reviews 18 previously reported patients who presented with spastic para- or tetraplegia due to myelopathy with and without vision loss and were ultimately diagnosed with profound biotinidase deficiency, but often after a prolonged diagnostic odyssey resulting in residual neurological damage or even death. I was particularly struck with the great variability in age of onset (from 16 months to 22 years), as well as with the fact that some of the patients were found to have elevated oligoclonal bands and immunoglobulin G concentrations in their cerebral spinal fluid, misleadingly suggesting an inflammatory diagnosis. The article makes a convincing case for considering biotinidase deficiency early in any patient with myelopathy (including adult patients), even in the presence of elevated oligoclonal bands and immunoglobulin G concentrations.

Wolf B (2015) Biotinidase deficiency should be considered in individuals exhibiting myelopathy with or without and vision loss. Mol Genet Metab 116: 113-118.