Mitochondrial DNA depletion: Prevalence in a pediatric population referred for neurologic evaluation

doi:10.1016/0887-8994(96)00018-5

Pediatric Neurology

Volume 14, Issue 3, April 1996, Pages 203-210

https://doi.org/10.1016/0887-8994(96)00018-5 Get rights and content

Abstract

Mitochondrial DNA depletion is a quantitative disorder of mtDNA, characterized by tissue-specific reductions in mtDNA copy number, that presents in infancy or early childhood. It is most likely transmitted as an autosomal recessive trait, although about half of the described cases are sporadic. To estimate its prevalence we measured relative mtDNA copy number (mtDNA:18S rDNA ratio) by Southern blot analysis in muscle biopsy samples from all children with compatible histories referred between 1983 and 1994. Of the 304 biopsies evaluated, 54 met the study criteria. We found 6 patients (2 male, 4 female) with mtDNA depletion (relative mtDNA copy number 7.9–33.2% of control). Their clinical course and findings were heterogeneous, however all but one manifested weakness, hypotonia, and developmental delay. Clinical severity was not obviously related to the degree of mtDNA depletion. No patient had ragged-red fibers, although 2 had a lipid storage myopathy. Immunofluorescence with antibodies to double-stranded DNA, COX IV, and COX II demonstrated homogeneously reduced reactivity to all three antibodies compared with control. mtDNA depletion may be a relatively common neurogenetic disorder of infancy and early childhood and should be considered in children with unexplained weakness, hypotonia, or developmental delay.

References (17)

E.A. Schon et al.
Mitochondrial encephalomyopathies: Clinical and molecular analysis
J Bioenerg Biomembr
(1994)
M.D. Brown et al.
Molecular basis of mitochondrial DNA disease
J Bioenerg Biomembr
(1994)
Ag Bodnar et al.
Nuclear complementation restores mtDNA levels in cultured cells from a patient with mtDNA depletion
Am J Hum Genet
(1993)
R.N. Boustany et al.
Mitochondrial cytochrome deficiency presenting as a myopathy with hypotonia, external ophthalmoplegia, and lactic acidosis in an infant and as fatal hepatopathy in a second cousin
Ann Neurol
(1983)
C.T. Moraes et al.
mtDNA depletion with variable tissue expression: A novel genetic abnormality in mitochondrial diseases
Am J Hum Genet
(1991)
N. Telerman-Toppet et al.
Fatal cytochrome c oxidase-deficient myopathy of infancy associated with mtDNA depletion. Differential involvement of skeletal muscle and cultured fibroblasts
J Inherited Metab Dis
(1992)
H.-J. Tritschler et al.
Mitochondrial myopathy of childhood associated with depletion of mitochondrial DNA
Neurology
(1992)
M. Mazziotta et al.
Fatal infantile liver failure associated with mitochondrial DNA depletion
J Pediatr
(1992)

There are more references available in the full text version of this article.

Cited by (66)

Mitochondrial DNA: Structure, genetics, replication and defects
2019, Mitochondria in Obesity and Type 2 Diabetes: Comprehensive Review on Mitochondrial Functioning and Involvement in Metabolic Diseases
Since the discovery of DNA in mitochondria in 1963, our knowledge of the structure, function, and cellular mechanisms involved in the replication and transmission of this mitochondrial DNA (mtDNA) has progressed spectacularly. We now know that human mtDNA is a circular duplex molecule of 16,569 base pairs that is present in multiple copies in the cell, contains genes indispensable for the biosynthesis of the oxidative phosphorylation enzymes, and shows maternal inheritance. With the advance of molecular genetic techniques in the late 1980s, it became clear that mutations in mtDNA are a common cause of a number of genetic diseases with variable clinical expression. Most often, both mutant and wild-type mtDNA copies co-exist within the same cell, a phenomenon known as heteroplasmy. Symptoms manifest only when the proportion of mutated mtDNA in a tissue passes a critical threshold. Women carrying heteroplasmic mutations will pass on different mutation loads to their offspring, leading to substantial phenotypic heterogeneity among siblings. Because mtDNA diseases have no cure, the current focus of research is on risk reduction strategies for women to prevent germline transmission of mtDNA mutations.
Hypotonia and Weakness: Level of the Muscle
2018, Volpe's Neurology of the Newborn
Disorders of muscle account for a substantial proportion of infants affected with hypotonia and weakness. Although a relatively large number of myopathic disorders may cause manifestations in the neonatal period, only a few disorders account for most of the cases observed. Myotonic dystrophy is the most frequent. Myopathic disorders with nondiagnostic histology include congenital muscular dystrophy, facioscapulohumeral dystrophy, polymyositis, and minimal change myopathy; those with a diagnostic histology include core myopathies, nemaline myopathy, myotubular myopathy, congenital fiber type disproportion, mitochondrial myopathies, and metabolic myopathies. Several disorders of the neuromuscular apparatus are restricted to a small portion of the motor system; restricted disorders that are not established as caused principally by trauma are considered in this chapter. Detection of any of these disorders is valuable for purposes of genetic counseling, determination of prognosis, and institution of therapy.
Effects of ginseng on peripheral blood mitochondrial DNA copy number and hormones in men with metabolic syndrome: A randomized clinical and pilot study
2016, Complementary Therapies in Medicine
Citation Excerpt :
Mitochondrial dysfunction has been implicated in a variety of diseases, such as cancer, aging, neurodegeneration, and metabolic syndrome.13 Altered mitochondrial DNA (mtDNA) copy number regulation can lead to diseases such as neurogenic disorders and multiple sclerosis.14 Additionally, a decrease in mtDNA copy number has been related with type 2 diabetes and dyslipidaemia.15,16
It has been observed that mitochondrial dysfunction is associated with an increased risk of metabolic syndrome. There is growing evidence that hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis and hormone (testosterone and growth hormone) deficiency may lead to metabolic syndrome. Recent studies have reported that ginseng treatment improves mitochondrial and HPA-axis function and increases anabolic hormone secretion.
The objective of this study was to investigate the effect of red ginseng (RG) on metabolic syndrome, hormones, and mitochondrial function using leukocyte mitochondrial DNA copy number in men with metabolic syndrome.
We performed a randomized, double-blind, placebo-controlled study in 62 subjects who were not taking drugs that could affect their metabolic function. A total of 62 men with metabolic syndrome were randomly assigned to either an RG group (3.0 g/day) or a placebo group for 4 weeks. We analyzed changes in metabolic syndrome components, leukocyte mitochondrial DNA copy number, hormones (total testosterone, IGF-1, cortisol, and DHEAS) and inflammatory markers (C-reactive protein, ferritin) from baseline to 4 weeks.
Significant improvement in mitochondrial function (95% CI −44.9 to −1.3) and an increase in total testosterone (95% CI −70.1 to −1.0) and IGF-1(P = 0.01) levels were observed in the RG group when compared with the placebo group. Diastolic blood pressure (95% CI 2.0–9.4) and serum cortisol (95% CI 1.1–5.5) significantly decreased in the RG group.
We found evidence that RG had a favorable effect on mitochondrial function and hormones in men with metabolic syndrome.
Mitochondrial DNA copy number is reduced in male combat veterans with PTSD
2016, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Citation Excerpt :
MtDNAcn is therefore considered a marker of mitochondrial energetic function (Clay Montier et al., 2009; Moyes et al., 1998) and biogenesis (Clay Montier et al., 2009; Lee and Wei, 2005). While the exact meaning/significance of mtDNAcn is still not completely known, the importance of mtDNAcn maintenance for cell physiology and homeostasis is underscored by the evidence of altered mtDNAcn associated with diverse types of human disease, including developmental delays in early childhood (Macmillan and Shoubridge, 1996), multiple sclerosis (Blokhin et al., 2008), renal and breast cancers (Xing et al., 2008; Yu et al., 2007), liver disease (Morten et al., 2007), biliary atresia (Tiao et al., 2007), type 2 diabetes (Choi et al., 2001; Lee et al., 1998), insulin resistance (Choi et al., 2001; Lee et al., 1998), cardiomyopathy (Bai and Wong, 2005) and metabolic syndrome (Kim et al., 2012). Also, certain genetic defects that impair mitochondrial biogenesis can lead to depletion of mtDNA, which dramatically reduces mitochondrial energy production capacity leading to multisystemic disease (Al-Hussaini et al., 2014; Hudson and Chinnery, 2006).
Mitochondrial abnormalities may be involved in PTSD, although few studies have examined this. Mitochondrial DNA copy number (mtDNAcn) in blood cells is an emerging systemic index of mitochondrial biogenesis and function. The present study assessed mtDNAcn in male combat-exposed veterans with PTSD compared to those without PTSD as well as its correlation with clinical scales.
mtDNAcn was assessed with a TaqMan multiplex assay in granulocytes of 43 male combat veterans with (n = 43) or without (n = 44) PTSD. Twenty of the PTSD subjects had co-morbid major depressive disorder (MDD). The Clinician Administered PTSD Scale (CAPS), the Positive and Negative Affect Schedule (PANAS), the Early Trauma Inventory (ETI) and the Beck Depression Inventory II (BDI-II) were used for the clinical assessments. All analyses were corrected for age and BMI.
mtDNAcn was significantly lower in subjects with PTSD (p < 0.05). Within the PTSD group, those with moderate PTSD symptom severity had relatively higher mtDNAcn than those with mild or severe symptoms (p < 0.01). Within the PTSD group, mtDNAcn was positively correlated with PANAS positive subscale ratings (p < 0.01) but was not significantly correlated with PANAS negative subscale, ETI or BDI-II ratings.
This study provides the first evidence of: (i) a significant decrease of mtDNAcn in combat PTSD, (ii) a possible “inverted-U” shaped relationship between PTSD symptom severity and mtDNAcn within PTSD subjects, and (iii) a direct correlation of mtDNAcn with positive affectivity within PTSD subjects. Altered mtDNAcn in PTSD may reflect impaired energy metabolism, which might represent a novel aspect of its pathophysiology.
Leukocyte mitochondrial DNA (mtDNA) content is associated with depression in old women
2011, Archives of Gerontology and Geriatrics
Citation Excerpt :
In addition, a recent study reported that maintenance of mtDNA content is essential for mitochondrial function and cell growth (Jeng et al., 2008). The mtDNA-depletion was reported as a quantitative disorder of mtDNA, characterized by decreased muscle strength, hypotonia and developmental delay due to a congenital deficiency of mtDNA (Macmillan and Shoubridge, 1996). In addition, it has been reported in several clinical studies that the decrease of mtDNA content is related with type 2 diabetes (Lee et al., 1998), microalbuminuria (Lee et al., 2009), breast cancer (Fan et al., 2009), colon cancer (Lin et al., 2008), and renal cell carcinoma (Xing et al., 2008).
The purpose of this study was to investigate whether mitochondrial DNA (mtDNA) content of peripheral blood leukocyte is related to depression in community-dwelling old women. A total of 142 community-dwelling women, older than 60 years, were included in the study. The mtDNA copy number, which represents the mtDNA content, was measured using real-time PCR methods. Patients with depression defined as the subjects whose 15-question geriatric depression scale (GDS) score was ≥8 or who were taking anti-depressant medication. We also measured cognitive function, physical performances (gait speed, chair-stand times, tandem standing times) and metabolic parameters. The depression group had a significantly lower mtDNA copy number than the control group (71.5 vs. 107.3; interquartile range (IQR) = 42.7–116.0 vs. 51.7–202.1; p = 0.028). The Korean version of the mini mental state examination (K-MMSE) score and physical performance score were significantly lower in the depression group than in the control group (p = 0.041, and p = 0.002, respectively). After adjustment for confounding factors using multiple logistic regression analysis, mtDNA copy number was significantly related to depression (p = 0.025). We demonstrated that low leukocyte mtDNA content is related to depression in community dwelling old women. This finding suggests that mitochondrial dysfunction could be a mechanism of geriatric depression.
Number matters: control of mammalian mitochondrial DNA copy number
2009, Journal of Genetics and Genomics
Regulation of mitochondrial biogenesis is essential for proper cellular functioning. Mitochondrial DNA (mtDNA) depletion and the resulting mitochondrial malfunction have been implicated in cancer, neurodegeneration, diabetes, aging, and many other human diseases. Although it is known that the dynamics of the mammalian mitochondrial genome are not linked with that of the nuclear genome, very little is known about the mechanism of mtDNA propagation. Nevertheless, our understanding of the mode of mtDNA replication has advanced in recent years, though not without some controversies. This review summarizes our current knowledge of mtDNA copy number control in mammalian cells, while focusing on both mtDNA replication and turnover. Although mtDNA copy number is seemingly in excess, we reason that mtDNA copy number control is an important aspect of mitochondrial genetics and biogenesis and is essential for normal cellular function.

View all citing articles on Scopus

¹: The authors thank Dr. George Karpati for graciously making his muscle biopsy bank and archives available. We also thank Dr. Russell Doolittle for donating the anti-COX II antibody and Dr. Bernhard Kadenbach for donating the anti-COX IV antibody. Katherine Fu and Timothy Johns provided expert technical assistance.

View full text

Original article : Watters FestchriftMitochondrial DNA depletion: Prevalence in a pediatric population referred for neurologic evaluation

Abstract

Mitochondrial encephalomyopathies: Clinical and molecular analysis

J Bioenerg Biomembr

Molecular basis of mitochondrial DNA disease

J Bioenerg Biomembr

Nuclear complementation restores mtDNA levels in cultured cells from a patient with mtDNA depletion

Am J Hum Genet

Mitochondrial cytochrome deficiency presenting as a myopathy with hypotonia, external ophthalmoplegia, and lactic acidosis in an infant and as fatal hepatopathy in a second cousin

Ann Neurol

mtDNA depletion with variable tissue expression: A novel genetic abnormality in mitochondrial diseases

Am J Hum Genet

Fatal cytochrome c oxidase-deficient myopathy of infancy associated with mtDNA depletion. Differential involvement of skeletal muscle and cultured fibroblasts

J Inherited Metab Dis

Mitochondrial myopathy of childhood associated with depletion of mitochondrial DNA

Neurology

Fatal infantile liver failure associated with mitochondrial DNA depletion

J Pediatr

Original article : Watters Festchrift
Mitochondrial DNA depletion: Prevalence in a pediatric population referred for neurologic evaluation