scholarly journals Endocrine Disorders in Primary Mitochondrial Disease

2018 ◽  
Vol 2 (4) ◽  
pp. 361-373 ◽  
Author(s):  
Iman S Al-Gadi ◽  
Richard H Haas ◽  
Marni J Falk ◽  
Amy Goldstein ◽  
Shana E McCormack
Keyword(s):  
Mitochondrial Disease ◽  
Nuclear Dna ◽  
Molecular Genetic ◽  
Point Mutations ◽  
High Risk Population ◽  
Endocrine Disorders ◽  
Screening Practices ◽  
Abnormal Growth ◽  
The North ◽  
Adult Participants

Abstract Context Endocrine disorders are common in individuals with mitochondrial disease. To develop evidence-based screening practices in this high-risk population, updated age-stratified estimates of the prevalence of endocrine conditions are needed. Objective To measure the point prevalence of selected endocrine disorders in individuals with mitochondrial disease. Design, Setting, and Patients The North American Mitochondrial Disease Consortium Patient Registry is a large, prospective, physician-curated cohort study of individuals with mitochondrial disease. Participants (n = 404) are of any age, with a diagnosis of primary mitochondrial disease confirmed by molecular genetic testing. Main Outcome Measures Age-specific prevalence of diabetes mellitus (DM), abnormal growth and sexual maturation (AGSM), hypoparathyroidism, and hypothyroidism. Results The majority of our sample was pediatric (<18 years; 60.1%), female (56.9%), and white (85.9%). DM affected 2% of participants aged <18 years [95% confidence interval (CI): 0.4% to 5.7%] and 24.4% of adult participants (95% CI: 18.6% to 30.9%). DM prevalence was highest in individuals with mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes syndrome (MELAS; 31.9%, of whom 86.2% had the m.3243A>G mutation). DM occurred more often with mitochondrial DNA defects (point mutations and/or deletions) than with nuclear DNA mutations (23.3% vs 3.7%, respectively; P < 0.001). Other prevalence estimates were 44.1% (95% CI: 38.8% to 49.6%) for AGSM; 0.3% (95% CI: 0% to 1.6%) for hypoparathyroidism; and 6.3% (95% CI: 4% to 9.3%) for hypothyroidism. Conclusion DM and AGSM are highly prevalent in primary mitochondrial disease. Certain clinical mitochondrial syndromes (MELAS and Kearns-Sayre/Pearson syndrome spectrum disorders) demonstrated a higher burden of endocrinopathies. Clinical screening practices should reflect the substantial prevalence of endocrine disorders in mitochondrial disease.

Le encefalomiopatie mitocondriali

1996 ◽  
Vol 9 (6) ◽  
pp. 775-780 ◽  
Author(s):  
E. Ciceri ◽  
I. Moroni ◽  
G. Uziel ◽  
M. Savoiardo
Keyword(s):  
Mitochondrial Dna ◽  
Respiratory Chain ◽  
Mitochondrial Disease ◽  
Nuclear Dna ◽  
Molecular Genetic ◽  
Neuromuscular Diseases ◽  
Disease Classification ◽  
Respiratory Chain Complexes ◽  
Enzyme Defect ◽  
Mitochondrial Encephalomyopathies

The mitochondrial encephalomyopathies are relatively rare neuromuscular diseases clinically characterised by myopathy and encephalopathy caused by structurally or functionally impaired mitochondria. The biochemical hallmark of this group of disorders is impaired mitochondrial energy production: Kreb's cycle, respiratory chain, oxidative phosphorylation and beta-oxidation of fatty acids. The presence of lactic acidosis and ragged red fibres, i.e. subsarcolemmal accumulations of abnormally sized mitochondria are highly indicative findings for mitochondrial disease. Classification and diagnostic criteria are based on biochemical findings with a search for specific enzyme deficit and molecular genetic information. Molecular genetic studies aim to identify the mitochondrial DNA changes responsible for the enzyme defect. Ragged red fibres are not essential for diagnosis as they are not present in some diseases. In rare cases, mitochondrial diseases are caused by nuclear DNA defects or, more commonly a mitochondrial DNA deficit. Diagnosis may prove difficult given the pathogenetic complexity and clinical and phenotypical variability of these conditions. Despite indirect symptoms of mitochondrial disease, the enzyme defect and genetic alteration cannot be identified in some cases. The mitochondrial encephalopathies can be classified according to the metabolic pathways involved into impaired transport ot uptake of energy, impaired Kreb's cycle or respiratory chain complexes or complex defects due to mitochondrial DNA changes.

Mitochondrial molecular genetic results in a South African cohort: divergent mitochondrial and nuclear DNA findings

2020 ◽  
pp. jclinpath-2020-207026
Author(s):  
Surita Meldau ◽  
Elizabeth Patricia Owen ◽  
Kashief Khan ◽  
Gillian Tracy Riordan
Keyword(s):  
South Africa ◽  
Mitochondrial Disease ◽  
Nuclear Dna ◽  
Molecular Genetic ◽  
Mitochondrial Diseases ◽  
Pathogenic Variant ◽  
Sub Saharan Africa ◽  
Inborn Errors ◽  
Birth Prevalence ◽  
Positive Results

AimsMitochondrial diseases form one of the largest groups of inborn errors of metabolism. The birth prevalence is approximately 1/5000 in well-studied populations, but little has been reported from Sub-Saharan Africa. The aim of this study was to describe the genetics underlying mitochondrial disease in South Africa.MethodsAn audit was performed on all mitochondrial disease genetic testing performed in Cape Town, South Africa.ResultsOf 1614 samples tested for mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) variants in South Africa between 1994 and 2019, there were 155 (9.6 %) positive results. Pathogenic mtDNA variants accounted for 113 (73%)/155, from 96 families. Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes, 37 (33%)/113, Leber’s hereditary optic neuropathy, 26 (23%)/113, and single large mtDNA deletions, 22 (20%)/113, accounted for 76%. Thirty eight of 42 nDNA-positive results were homozygous for the MPV17 pathogenic variant c.106C>T (p.[Gln36Ter, Ser25Profs*49]) causing infantile neurohepatopathy, one of the largest homozygous groups reported in the literature. The other nDNA variants were in TAZ1, CPT2, BOLA3 and SERAC1. None were identified in SURF1, POLG or PDHA1.ConclusionsFinding a large group with a homozygous nuclear pathogenic variant emphasises the importance of looking for possible founder effects. The absence of other widely described pathogenic nDNA variants in this cohort may be due to reduced prevalence or insufficient testing. As advances in therapeutics develop, it is critical to develop diagnostic platforms on the African subcontinent so that population-specific genetic variations can be identified.

scholarly journals Risk of cardiac manifestations in adult mitochondrial disease caused by nuclear genetic defects

Open Heart ◽  
2021 ◽  
Vol 8 (1) ◽  
pp. e001510
Author(s):  
Albert Zishen Lim ◽  
Daniel M Jones ◽  
Matthew G D Bates ◽  
Andrew M Schaefer ◽  
John O'Sullivan ◽  
...  
Keyword(s):  
Mitochondrial Disease ◽  
Nuclear Dna ◽  
Laboratory Data ◽  
Nuclear Genome ◽  
Nuclear Gene ◽  
Left Ventricular ◽  
Adult Patients ◽  
Limited Information ◽  
Cardiac Abnormalities ◽  
Cardiac Manifestations

ObjectiveRegular cardiac surveillance is advocated for patients with primary mitochondrial DNA disease. However, there is limited information to guide clinical practice in mitochondrial conditions caused by nuclear DNA defects. We sought to determine the frequency and spectrum of cardiac abnormalities identified in adult mitochondrial disease originated from the nuclear genome.MethodsAdult patients with a genetically confirmed mitochondrial disease were identified and followed up at the national clinical service for mitochondrial disease in Newcastle upon Tyne, UK (January 2009 to December 2018). Case notes, molecular genetics reports, laboratory data and cardiac investigations, including serial electrocardiograms and echocardiograms, were reviewed.ResultsIn this cohort-based observational study, we included 146 adult patients (92 women) (mean age 53.6±18.7 years, 95% CI 50.6 to 56.7) with a mean follow-up duration of 7.9±5.1 years (95% CI 7.0 to 8.8). Eleven different nuclear genotypes were identified: TWNK, POLG, RRM2B, OPA1, GFER, YARS2, TYMP, ETFDH, SDHA, TRIT1 and AGK. Cardiac abnormalities were detected in 14 patients (9.6%). Seven of these patients (4.8%) had early-onset cardiac manifestations: hypertrophic cardiomyopathy required cardiac transplantation (AGK; n=2/2), left ventricular (LV) hypertrophy and bifascicular heart block (GFER; n=2/3) and mild LV dysfunction (GFER; n=1/3, YARS2; n=1/2, TWNK; n=1/41). The remaining seven patients had acquired heart disease most likely related to conventional cardiovascular risk factors and presented later in life (14.6±12.8 vs 55.1±8.9 years, p<0.0001).ConclusionsOur findings demonstrate that the risk of cardiac involvement is genotype specific, suggesting that routine cardiac screening is not indicated for most adult patients with nuclear gene-related mitochondrial disease.

scholarly journals Androgenic-Induced Transposable Elements Dependent Sequence Variation in Barley

2021 ◽  
Vol 22 (13) ◽  
pp. 6783
Author(s):  
Renata Orłowska ◽  
Katarzyna A. Pachota ◽  
Wioletta M. Dynkowska ◽  
Agnieszka Niedziela ◽  
Piotr T. Bednarek
Keyword(s):  
Dna Methylation ◽  
Transposable Elements ◽  
Dna Sequence ◽  
Sequence Variation ◽  
Nuclear Dna ◽  
Point Mutations ◽  
Mobile Elements ◽  
Dna Demethylation ◽  
Plant Genome

A plant genome usually encompasses different families of transposable elements (TEs) that may constitute up to 85% of nuclear DNA. Under stressful conditions, some of them may activate, leading to sequence variation. In vitro plant regeneration may induce either phenotypic or genetic and epigenetic changes. While DNA methylation alternations might be related, i.e., to the Yang cycle problems, DNA pattern changes, especially DNA demethylation, may activate TEs that could result in point mutations in DNA sequence changes. Thus, TEs have the highest input into sequence variation (SV). A set of barley regenerants were derived via in vitro anther culture. High Performance Liquid Chromatography (RP-HPLC), used to study the global DNA methylation of donor plants and their regenerants, showed that the level of DNA methylation increased in regenerants by 1.45% compared to the donors. The Methyl-Sensitive Transposon Display (MSTD) based on methylation-sensitive Amplified Fragment Length Polymorphism (metAFLP) approach demonstrated that, depending on the selected elements belonging to the TEs family analyzed, varying levels of sequence variation were evaluated. DNA sequence contexts may have a different impact on SV generated by distinct mobile elements belonged to various TE families. Based on the presented study, some of the selected mobile elements contribute differently to TE-related SV. The surrounding context of the TEs DNA sequence is possibly important here, and the study explained some part of SV related to those contexts.

Abnormal growth in mitochondrial disease

2009 ◽  
Vol 98 (3) ◽  
pp. 553-554 ◽  
Author(s):  
S Wolny ◽  
R McFarland ◽  
P Chinnery ◽  
T Cheetham
Keyword(s):  
Mitochondrial Disease ◽  
Abnormal Growth

scholarly journals Identification of a Large Deletion, Spanning Exons 4 to 11 of the Human Factor XIIIA Gene, in a Factor XIII-Deficient Family

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 149-153 ◽  
Author(s):  
Rashida Anwar ◽  
Krzysztof J.A. Miloszewski ◽  
Alexander F. Markham
Keyword(s):  
Autosomal Recessive ◽  
Molecular Genetic ◽  
Point Mutations ◽  
Autosomal Recessive Disorder ◽  
Large Deletion ◽  
Factor Xiiia ◽  
Paternal Allele ◽  
Bleeding Tendency ◽  
Genetic Studies ◽  
Polymerase Chain

Inherited deficiency of factor XIIIA subunit (FXIIIA) is an autosomal recessive disorder that is characterized by a life-long bleeding tendency and complications in wound healing. Molecular genetic studies have shown the deficiency can be due to small sequence changes within the FXIIIA gene, such as point mutations or microdeletions. On molecular analysis of the FXIIIA gene in an FXIII-deficient patient, of United Kingdom origin, we identified a putative homozygous missense mutation, Arg408Gln. However, the father of this patient is homozygous normal for arginine at codon 408. Having proved paternity in this pedigree by microsatellite analysis, we examined the FXIIIA RNA of the patient by reverse transcriptase-polymerase chain reaction and found the paternal allele to lack exons 4 through 11 inclusive. Hence, a huge deletion extending from intron 3 to intron 11 and the Arg408Gln mutation are jointly responsible for FXIIIA deficiency in this family. This is the first finding of such a large deletion in the FXIIIA gene.

Species boundaries in the Rana arfaki group (Anura: Ranidae) and phylogenetic relationships to other New Guinean Rana

Zootaxa ◽  
2010 ◽  
Vol 2496 (1) ◽  
pp. 49 ◽  
Author(s):  
STEPHEN C. DONNELLAN ◽  
KEN P. APLIN ◽  
TERRY BERTOZZI
Keyword(s):  
Genetic Differentiation ◽  
Genetic Relationships ◽  
Molecular Genetic ◽  
Geographic Area ◽  
The North ◽  
Morphological Differences ◽  
Digital Disc ◽  
High Level ◽  
North And South ◽  
Central Cordillera

Allozyme electrophoresis is used to explore molecular genetic relationships within the Rana arfaki group and between this group and selected lineages of New Guinean Rana. Rana jimiensis is confirmed as a species distinct from R. arfaki and its range in Papua New Guinea is extended to the Southern Highlands Province and the north-coastal ranges in Sandaun Province. Rana arfaki and R. jimiensis show a high level of genetic differentiation maintained across a wide geographic area and show consistent morphological differences in head shape, tympanum size, degree of digital disc dilation and extent of sexual dimorphism. The two species occur syntopically on the Papuan Plateau, Southern Highlands Province, and are regionally sympatric in Sandaun Province. The observed level of genetic differentiation is equivalent to that reported previously between regionally sympatric members of the Rana papua group. Populations of R. jimiensis from north and south of the central cordillera show no obvious morphological and only minor genetic differentiation. In contrast, R. arfaki shows considerable geographic variation in both morphology and allozymes and may include two or more regionally distinctive forms.

Phylogeny, diversity, and species delimitation of the North American Round-Nosed Minnows (Teleostei: Dionda), as inferred from mitochondrial and nuclear DNA sequences

2012 ◽  
Vol 62 (1) ◽  
pp. 427-446 ◽  
Author(s):  
Susana Schönhuth ◽  
David M. Hillis ◽  
David A. Neely ◽  
Lourdes Lozano-Vilano ◽  
Anabel Perdices ◽  
...  
Keyword(s):  
Dna Sequences ◽  
North American ◽  
Species Delimitation ◽  
Nuclear Dna ◽  
The North

Mitochondrial diseases and the kidney

2015 ◽  
Author(s):  
Andrew Hall ◽  
Shamima Rahman
Keyword(s):  
Nephrotic Syndrome ◽  
Mitochondrial Disease ◽  
Nuclear Dna ◽  
Collecting Duct ◽  
Immunosuppressive Agents ◽  
Complex Function ◽  
The Body ◽  
Mitochondrial Morphology ◽  
Coq10 Deficiency ◽  
Proximal Tubulopathy

Mitochondrial disease can affect any organ in the body including the kidney. As increasing numbers of patients with mitochondrial disease are either surviving beyond childhood or being diagnosed in adulthood, it is important for all nephrologists to have some understanding of the common renal complications that can occur in these individuals. Mitochondrial proteins are encoded by either mitochondrial or nuclear DNA (mtDNA and nDNA, respectively); therefore, disease causing mutations may be inherited maternally (mtDNA) or autosomally (nDNA), or can arise spontaneously. The commonest renal phenotype in mitochondrial disease is proximal tubulopathy (Fanconi syndrome in the severest cases); however, as all regions of the nephron can be affected, from the glomerulus to the collecting duct, patients may also present with proteinuria, decreased glomerular filtration rate, nephrotic syndrome, water and electrolyte disorders, and renal tubular acidosis. Understanding of the relationship between underlying genotype and clinical phenotype remains incomplete in mitochondrial disease. Proximal tubulopathy typically occurs in children with severe multisystem disease due to mtDNA deletion or mutations in nDNA affecting mitochondrial function. In contrast, glomerular disease (focal segmental glomerulosclerosis) has been reported more commonly in adults, mainly in association with the m.3243A<G point mutation. Co-enzyme Q10 (CoQ10) deficiency has been particularly associated with podocyte dysfunction and nephrotic syndrome in children. Underlying mitochondrial disease should be considered as a potential cause of unexplained renal dysfunction; clinical clues include lack of response to conventional therapy, abnormal mitochondrial morphology on kidney biopsy, involvement of other organs (e.g. diabetes, cardiomyopathy, and deafness) and a maternal family history, although none of these features are specific. The diagnostic approach involves acquiring tissue (typically skeletal muscle) for histological analysis, mtDNA screening and oxidative phosphorylation (OXPHOS) complex function tests. A number of nDNA mutations causing mitochondrial disease have now been identified and can also be screened for if clinically indicated. Management of mitochondrial disease requires a multidisciplinary approach, and treatment is largely supportive as there are currently very few evidence-based interventions. Electrolyte deficiencies should be corrected in patients with urinary wasting due to tubulopathy, and CoQ10 supplementation may be of benefit in individuals with CoQ10 deficiency. Nephrotic syndrome in mitochondrial disease is not typically responsive to steroid therapy. Transplantation has been performed in patients with end-stage kidney disease; however, immunosuppressive agents such as steroids and tacrolimus should be used with care given the high incidence of diabetes in mitochondrial disease.

Glucokinase and glucose homeostasis: proven concepts and new ideas

2005 ◽  
Vol 33 (1) ◽  
pp. 306-310 ◽  
Author(s):  
D. Zelent ◽  
H. Najafi ◽  
S. Odili ◽  
C. Buettger ◽  
H. Weik-Collins ◽  
...  
Keyword(s):  
Glucose Sensor ◽  
Molecular Genetic ◽  
Point Mutations ◽  
Laboratory Animals ◽  
Glycolytic Flux ◽  
Β Cells ◽  
Metabolic Switch ◽  
Pharmacological Agents ◽  
Genetic Characteristics ◽  
Glucose Homoeostasis

The enzyme GK (glucokinase), which phosphorylates glucose to form glucose 6-phosphate, serves as the glucose sensor of insulin-producing β-cells. GK has thermodynamic, kinetic, regulatory and molecular genetic characteristics that are ideal for its glucose sensor function and allow it to control glycolytic flux of the β-cells as indicated by control-, elasticity- and response-coefficients close to or larger than 1.0. GK operates in tandem with the K+ and Ca2+ channels of the β-cell membrane, resulting in a threshold for glucose-stimulated insulin release of approx. 5 mM, which is the set point of glucose homoeostasis for most laboratory animals and humans. Point mutations of GK cause ‘glucokinase disease’ in humans, which includes hypo- and hyper-glycaemia syndromes resulting from activating or inactivating mutations respectively. GK is allosterically activated by pharmacological agents (called GK activators), which lower blood glucose in normal animals and animal models of T2DM. On the basis of crystallographic studies that identified a ligand-free ‘super-open’ and a liganded closed structure of GK [Grimsby, Sarabu, Corbett and others (2003) Science 301, 370–373; Kamata, Mitsuya, Nishimura, Eiki and Nagata (2004) Structure 12, 429–438], on thermostability studies using glucose or mannoheptulose as ligands and studies showing that mannoheptulose alone or combined with GK activators induces expression of GK in pancreatic islets and partially preserves insulin secretory competency, a new hypothesis was developed that GK may function as a metabolic switch per se without involvement of enhanced glucose metabolism. Current research has the goal to find molecular targets of this putative ‘GK-switch’. The case of GK research illustrates how basic science may culminate in therapeutic advances of human medicine.

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