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Brain MRI in patient 8 (Alpers-Huttenlocher syndrome). The patient was a compound heterozygote for the p.W748S/ D930N in the pol-g A protein. The same sequences of the brain are shown at different ages. (A, B) Faint hyperintensity with mild swelling of both thalami. (C, D) Bright signal in antero-and postero-lateral thalami. (E, F) Reduction of water diffusion in both thalami, with sparing of the medial nuclei. Note the evolution of the lesions from 13 to 15 months of age
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Mitochondrial DNA depletion syndromes (MDSs) form a group of autosomal recessive disorders characterized by profoundly decreased mitochondrial DNA copy numbers in affected tissues. Three main clinical presentations are known: myopathic, encephalomyopathic and hepatocerebral. The first is associated with mutations in thymidine kinase 2 (TK2) and p53...
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... mented in plasma, as well as high lactate in the CSF. The EEG showed diffuse disorganization of basal activity and multiple foci of paroxysmal activity. Seizures were partially controlled by a combination of phenobarbital, midazolam and propofol. Brain MRI at 13 months showed symmetrical lesions of both thalami with sparing of the medial nuclei (Fig. 4). A muscle biopsy showed a partial reduction of complex III and marked reduction of pyruvate dehydrogenase (PDH) activity. In the following months, she had numerous episodes of status epilepticus and epilepsia partialis continua. A second MRI at 15 months showed progression of the brain lesions (Fig. 4). High levels of transaminases, ...
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... thalami with sparing of the medial nuclei (Fig. 4). A muscle biopsy showed a partial reduction of complex III and marked reduction of pyruvate dehydrogenase (PDH) activity. In the following months, she had numerous episodes of status epilepticus and epilepsia partialis continua. A second MRI at 15 months showed progression of the brain lesions (Fig. 4). High levels of transaminases, hypocoagulation, low plasma protein levels and ascites were accompanied by dramatic worsening of the neurological symptoms, leading to death at 19 months of age. Autopsy examination was not ...
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Rationale:
Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) are thought to be rarely accompanied by macroangiopathy. We reported a case of MELAS that presented right distal internal carotid arterial (ICA) stenosis and reviewed 12 similar previously reported cases involving intracranial large blood vessels.
Patient co...
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... Mitochondrial DNA depletion syndrome (MDS) is caused by a severe reduction in mtDNA associated with tissue-specific symptoms which appear very early in development. These disorders have mutations in genes encoded by the nucleus and involved in nucleotide metabolism, such as TK2, SUCLA2, SUCLG1, RRM2B, FBXL4, AGK, DGUOK, SSBP1, and TYMP, or nucleoid-associated genes such as POLG, TWNK, TFAM, and mtSSB (Spinazzola et al. 2009). Reports have also suggested that defects in proteins devoted to DNA packaging, translation apparatus, import machinery, and fission-fusion dynamics are likely to cause similar disruptions in copy number (Zhang and Singh 2014). ...
Mitochondrial DNA depletion syndromes (MDS) encompass a wide spectrum of rare genetic disorders caused by severe reduction in mitochondrial DNA (mtDNA), and exhibit heterogenous phenotypes classified as myopathic, encephalomyopathic, hepatocerebral, and neurogastrointestinal. Prognosis for such a spectrum of diseases is poor and is majorly dependent on symptomatic treatment and nutritional supplementation. Understanding the mechanistic aspect of mtDNA depletion can help bring forth a new era of medicine, moving beyond symptomatic treatment and focusing more on organelle-targeted therapies. In this review, we highlight some of the proposed mechanistic bases of mtDNA depletion and the latest therapeutic measures used to treat MDS.
... In mitochondrial DNA (mtDNA) depletion syndromes (MDDS), the loss of mtDNA content severely affects mitochondrial respiratory chain activity, thus impairing the energetic balance of either a specific tissue (most commonly muscle, liver and brain) or of multiple organs. [1] MDDS usually display neonatal or infantile-onset and a rapid progression, resulting in death in the first years of life. [2] Loss of function mutations have been detected in several genes encoding for proteins involved in mtDNA maintenance. ...
Mitochondrial DNA (mtDNA) depletion syndromes are disorders characterized by infantile-onset, severe progression, and the drastic loss of mtDNA content in affected tissues. In a patient who showed severe hypotonia, proximal tubulopathy and sensorineural hearing loss after birth, we observed severe mtDNA depletion and impaired respiratory chain activity in muscle due to heterozygous variants c.686G > T and c.551-2A > G in RRM2B, encoding the p53R2 subunit of the ribonucleotide reductase.
... Mutations within the TTN gene can cause myopathies with vast clinical presentations as they can disrupt titin synthesis in muscles (Savarese et al., 2018;Spinazzola et al., 2009). ...
Mitochondrion regulates cellular metabolism with the aid of its respiratory complexes; any defect within these complexes can result in mitochondrial malfunction and various conditions. One such mutation can occur in SLC25A10 , resulting in mitochondrial DNA depletion syndrome. It should be noted that the pattern of inheritance of this syndrome is autosomal recessive. However, we present a case with compound heterozygous mutations within this gene resulting in disease. An 18-year-old female was referred to our clinic due to menopause with a medical history of hearing loss, spasticity, hypotonia and quadriparesis. The child’s birth and development were uneventful until the initiation of movement reduction and hypotonia when she was 12 months old. Afterward, the hypotonia progressed to quadriparesis and spasticity throughout the years. Our patient became completely quadriplegic up to the age of 3 and became completely deaf at 10. Her puberty onset was at the age of 9, and no significant event took place until she was 17 years old when suddenly her periods, which were regular until that time, became irregular and ceased after a year; hence, a thorough evaluation began, but similar to her previous evaluations all tests were insignificant. Nonetheless, we suspected an underlying metabolic or genetic defect; thus, we ordered a whole-exome sequencing (WES) workup and found simultaneous heterozygous mutations within SLC25A10 , HFE and TTN genes that could explain her condition. When all other tests fail, and we suspect an underlying genetic or metabolic cause, WES can be of great value.
... The production of key subunits of mitochondrial respiratory chain complex and energy production require a sufficient amount of mtDNA. Deletion of mtDNA can lead to organ dysfunction as a result of insufficient synthesis of respiratory chain components (46)(47)(48). Commonly mutated genes include TK2, FBXL4, TYPM, AGK, and others. MDS is classified as four forms, which are myopathic form, encephalomyopathic form, hepatocerebral form, and neurogastrointestinal form (49). MDS is usually involved in multiple systems with muscle-related symptoms, such as dystonia and muscle atrophy (50,51). ...
Mitochondria is a ubiquitous, energy-supplying (ATP-based) organelle found in nearly all eukaryotes. It acts as a “power plant” by producing ATP through oxidative phosphorylation, providing energy for the cell. The bioenergetic functions of mitochondria are regulated by nuclear genes (nDNA). Mitochondrial DNA (mtDNA) and respiratory enzymes lose normal structure and function when nuclear genes encoding the related mitochondrial factors are impaired, resulting in deficiency in energy production. Massive generation of reactive oxygen species and calcium overload are common causes of mitochondrial diseases. The mitochondrial depletion syndrome (MDS) is associated with the mutations of mitochondrial genes in the nucleus. It is a heterogeneous group of progressive disorders characterized by the low mtDNA copy number. TK2, FBXL4, TYPM , and AGK are genes known to be related to MDS. More recent studies identified new mutation loci associated with this disease. Herein, we first summarize the structure and function of mitochondria, and then discuss the characteristics of various types of MDS and its association with cardiac diseases.
... An additional study that similarly screened a pool of MDDS myopathy patients for specific gene defects revealed 10% had pathogenic TK2 variants [31]. A third study found 18% of a diverse MDDS cohort had pathogenic TK2 mutations, while a minimum of 10% of MDDS myopathy patients and a maximum of 18% of all MDDS patients were found to have TK2d [38]. Based on the established prevalence rates for the larger categories of mitochondrial diseases referenced, one can estimate a minimum prevalence of TK2d at 600 patients and a maximum prevalence of 2700 TK2-deficient patients in the United States. ...
Defects in the replication, maintenance, and repair of mitochondrial DNA (mtDNA) constitute a growing and genetically heterogeneous group of mitochondrial disorders. Multiple genes participate in these processes, including thymidine kinase 2 (TK2) encoding the mitochondrial matrix protein TK2, a critical component of the mitochondrial nucleotide salvage pathway. TK2 deficiency (TK2d) causes mtDNA depletion, multiple deletions, or both, which manifest predominantly as mitochondrial myopathy. A wide clinical spectrum phenotype includes a severe, rapidly progressive, early onset form (median survival: < 2 years); a less severe childhood-onset form; and a late-onset form with a variably slower rate of progression. Clinical presentation typically includes progressive weakness of limb, neck, facial, oropharyngeal, and respiratory muscle, whereas limb myopathy with ptosis, ophthalmoparesis, and respiratory involvement is more common in the late-onset form. Deoxynucleoside monophosphates and deoxynucleosides that can bypass the TK2 enzyme defect have been assessed in a mouse model, as well as under open-label compassionate use (expanded access) in TK2d patients, indicating clinical efficacy with a favorable side-effect profile. This treatment is currently undergoing testing in clinical trials intended to support approval in the US and European Union (EU). In the early expanded access program, growth differentiation factor 15 (GDF-15) appears to be a useful biomarker that correlates with therapeutic response. With the advent of a specific treatment and given the high morbidity and mortality associated with TK2d, clinicians need to know how to recognize and diagnose this disorder. Here, we summarize translational research about this rare condition emphasizing clinical aspects.
... Typically, there is rapid progression of muscle weakness with respiratory failure and death within a few years of onset. Genes associated with this form are TK2 [14], RRM2B (p53R2) [15], DGUOK (dGK) [16]. ...
Mitochondrial and lysosomal dysfunction accounts for a large group of inherited metabolic
disorders most of which are due to a dysfunctional mitochondrial respiratory chain (MRC) leading
to defi cient energy production and defects in phagocytosis in endosomal-lysosomal pathway
respectively. MRC function depends on the coordinated expression of both nuclear (nDNA)
and mitochondrial (mtDNA) genomes. Thus, mitochondrial diseases can be caused by genetic
defects in either the mitochondrial or the nuclear genome, or in the cross-talk between the two.
The mitochondrial DNA depletion syndromes (MDSs) are a clinically heterogeneous group of
disorders with an autosomal recessive pattern of inheritance that have onset in infancy or early
childhood and are characterized by a reduced number of copies of mtDNA in aff ected tissues and
organs. In this review article, we summarized the spectrum of mtDNA depletion disorders along
with minor learning of lysosomal storage diseases. This current article off ers a perspective on
the role of genetics in medical practice and how this role may evolve over the next several years.
... All these mechanisms cause deficient turnover and/or segregation of mtDNA to daughter cells, leading to a decrease in its copy number. Ultimately, mtDNA depletion results in inadequate synthesis of respiratory chain complexes with consequent deficient energy production and organ dysfunction (Sarzi et al., 2007a;Spinazzola et al., 2009). ...
Mutations in the MPV17 gene are associated with hepatocerebral form of mitochondrial depletion syndrome. The mechanisms through which MPV17 mutations cause respiratory chain dysfunction and mtDNA depletion is still unclear. The MPV17 gene encodes an inner membrane mitochondrial protein that was recently described to function as a non-selective channel. Although its exact function is unknown, it is thought to be important in the maintenance of mitochondrial membrane potential (ΔΨm). To obtain more information about the role of MPV17 in human disease, we investigated the effect of MPV17 knockdown and of selected known MPV17 mutations associated with MPV17 disease in vitro. We used different approaches in order to evaluate the cellular consequences of MPV17 deficiency. We found that lower levels of MPV17 were associated with impaired mitochondrial respiration and with a quiescent energetic metabolic profile. All the mutations studied destabilized the protein, resulting in reduced protein levels. We also demonstrated that different mutations caused different cellular abnormalities, including increased ROS production, decreased oxygen consumption, loss of ΔΨm, and mislocalization of MPV17 protein. Our study provides novel insight into the molecular effects of MPV17 mutations and opens novel possibilities for testing therapeutic strategies for a devastating group of disorders.
... Mutations within the RRM2B gene result in a variety of inherited mitochondrial diseases either recessive or dominant and can be divided into 2 major types: diseases characterized by mtDNA depletion and diseases characterized by multiple deletions of the mtDNA. mtDNA depletion, where inheritance is autosomal recessive, is generally characterized by severe multisystemic manifestations such as encephalomyopathy with proximal renal tubulopathy usually fatal in early age [5][6][7][8][9][10]. However, multiple mtDNA deletions cause tissue-specific cytochrome c oxidase (COX) deficiency. ...
RRM2B gene encodes ribonucleoside-diphosphate reductase subunit M2 B, the p53-inducible small subunit (p53R2) of ribonucleotide reductase (RNR), an enzyme catalyzing dNTP synthesis for mitochondrial DNA. Defects in this gene may cause severe mitochondrial disease affecting mainly the nervous system. This study is aimed at examining the effect of deleterious nonsynonymous SNP (nsSNP) on the structure of the RRM2B protein, using a variety of prediction tools followed by a molecular modeling analysis. After using 13 algorithms, 19 nsSNPs were predicted deleterious. Among these variants, 18 decreased the protein stability and 16 were localized in very highly conserved regions. Protein 3D structure analysis showed that 18 variants changed amino acid interactions. These results concur with what has been found in experimental trials; 7 deleterious nsSNPs were previously reported in patients suffering from genetic disorders affecting the nervous system. Thus, our study will provide useful information to design more efficient and fast genetic tests to find RRM2B gene mutations.
... Similar to human mtDNA, chicken mtDNA encodes only 13 oxidative phosphorylation (OXPHOS) proteins, two rRNAs, and 22 tRNAs (Boore, 1999). Since the synthesis of mtDNA is essential for the subunits of OXPHOS proteins, insufficient mtDNA synthesis leads to organ dysfunction to trigger many syndromes in human (Spinazzola et al., 2009), such as mtDNA depletion syndromes (MDS), which are autosomal recessive disorders characterized by a reduction in mtDNA copy number in specific tissues (El-Hattab et al., 2017). A previous study has reported that an autosomal recessive mutation in TWNK is linked to MDS in human (Sarzi et al., 2007). ...
Runting and stunting syndrome (RSS), which is characterized by low body weight, generally occurs early in life and leads to considerable economic losses in the commercial broiler industry. Our previous study has suggested that RSS is associated with mitochondria dysfunction in sex-linked dwarf (SLD) chickens. However, the molecular mechanism of RSS remains unknown. Based on the molecular diagnostics of mitochondrial diseases, we identified a recessive mutation c. 409G > A (p. Ala137Thr) of Twinkle mitochondrial DNA helicase (TWNK) gene and mitochondrial DNA (mtDNA) depletion in RSS chickens’ livers from strain N301. Bioinformatics investigations supported the pathogenicity of the TWNK mutation that is located on the extended peptide linker of Twinkle primase domain and might further lead to mtDNA depletion in chicken. Furthermore, overexpression of wild-type TWNK increases mtDNA copy number, whereas overexpression of TWNK A137T causes mtDNA depletion in vitro. Additionally, the TWNK c. 409G > A mutation showed significant associations with body weight, daily gain, pectoralis weight, crureus weight, and abdominal fat weight. Taken together, we corroborated that the recessive TWNK c. 409G > A (p. Ala137Thr) mutation is associated with RSS characterized by mtDNA depletion in SLD chicken.
... AFP, α-fetoprotein; EB, elder brother; ES, elder sister; HCC, hepatocellular carcinoma; NA, not available; ND, not detected; YB, younger brother; YS, younger sister followed by MPV17 and DGUOK mutations, were the most common in European countries [14]. Meanwhile, another showed that MPV17 and DGUOK were the most, and second most, frequent genetic causes of MTDPS, respectively [15], although all parents of the patients in that study were consanguineous. ...
Background:
Hepatocerebral mitochondrial DNA depletion syndrome (MTDPS) is a disease caused by defects in mitochondrial DNA maintenance and leads to liver failure and neurological complications during infancy. Liver transplantation (LT) remains controversial due to poor outcomes associated with extrahepatic symptoms. The purposes of this study were to clarify the current clinical and molecular features of hepatocerebral MTDPS and to evaluate the outcomes of LT in MTDPS patients in Japan.
Results:
We retrospectively assessed the clinical and genetic findings, as well as the clinical courses, of 23 hepatocerebral MTDPS patients from a pool of 999 patients who were diagnosed with mitochondrial diseases between 2007 and 2019. Causative genes were identified in 18 of 23 patients: MPV17 (n = 13), DGUOK (n = 3), POLG (n = 1), and MICOS13 (n = 1). Eight MPV17-deficient patients harbored c.451dupC and all three DGUOK-deficient patients harbored c.143-307_170del335. The most common initial manifestation was failure to thrive (n = 13, 56.5%). The most frequent liver symptom was cholestasis (n = 21, 91.3%). LT was performed on 12 patients, including nine MPV17-deficient and two DGUOK-deficient patients. Among the 12 transplanted patients, five, including one with mild intellectual disability, survived; while seven who had remarkable neurological symptoms before LT died. Five of the MPV17-deficient survivors had either c.149G > A or c.293C > T.
Conclusions:
MPV17 was the most common genetic cause of hepatocerebral MTDPS. The outcome of LT for MTDPS was not favorable, as previously reported, however, patients harboring MPV17 mutations associated with mild phenotypes such as c.149G > A or c.293C > T, and exhibiting no marked neurologic manifestations before LT, had a better prognosis after LT.
