Sign in to use this feature.

Years

Between: -

Subjects

remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline

Journals

Article Types

Countries / Regions

Search Results (52)

Search Parameters:
Keywords = leigh syndrome

Order results
Result details
Results per page
Select all
Export citation of selected articles as:
22 pages, 2565 KiB  
Article
Efficacy and Safety of 5-Aminolevulinic Acid Hydrochloride Combined with Sodium Ferrous Citrate in Pediatric Patients with Leigh Syndrome and Central Nervous System Disorders: An Initial Exploratory Trial with a Double-Blind Placebo-Controlled Period, Followed by an Open-Label Period and a Subsequent Long-Term Administration Study
by Yuichi Abe, Toshimitsu Hamasaki, Jun Natsume, Yukiko Mogami, Kei Murayama, Hideaki Shiraishi, Yuki Abe, Satoko Kumada, Ryuta Tanaka, Kenji Ihara, Takafumi Sakakibara, Yasushi Okazaki, Hitoshi Nakagawa, Kiwamu Takahashi, Mitsugu Yamauchi, Motowo Nakajima and Akira Ohtake
Life 2025, 15(8), 1168; https://doi.org/10.3390/life15081168 - 23 Jul 2025
Viewed by 385
Abstract
An explorative study was conducted to evaluate the efficacy and safety of 5-aminolevulinic acid hydrochloride combined with sodium ferrous citrate (SPP-004) in 10 pediatric patients with Leigh syndrome (LS) aged 3–24 months in 10 institutions between December 2014 and July 2019. The patients [...] Read more.
An explorative study was conducted to evaluate the efficacy and safety of 5-aminolevulinic acid hydrochloride combined with sodium ferrous citrate (SPP-004) in 10 pediatric patients with Leigh syndrome (LS) aged 3–24 months in 10 institutions between December 2014 and July 2019. The patients were randomized and allocated to the SPP-004 or placebo group for a 12-week double-blind period, followed by a 12-week open-label period with SPP-004 and then a long-term study of up to 180 weeks. The efficacy and safety were evaluated using the Newcastle Pediatric Mitochondrial Disease Scale (NPMDS) and adverse events (AEs), respectively. No significant differences were found between groups in NPMDS scores, but prolonged SPP-004 treatment stabilized or improved scores. During the initial double-blind phase, the serum lactate levels increased in the placebo group but not in the SPP-004 group. Over the period of prolonged treatment with SPP-004, the average serum lactate level gradually decreased to a normal level. One patient died due to heart failure, presumably due to an underlying disease. Overall, 7 out of 10 patients received SPP-004 without developing severe AEs until the termination of the long-term study. Given the severe symptoms and poor prognosis of pediatric LS, NPMDS scores were indicative of stabilization in pediatric LS patients treated with SPP-004. Full article
(This article belongs to the Section Pharmaceutical Science)
Show Figures

Figure 1

13 pages, 2044 KiB  
Article
Exploring the Phenotypic Heterogeneity and Bioenergetic Profile of the m.13513G>A mtDNA Substitution: A Heteroplasmy Perspective
by Tatiana Krylova, Yulia Itkis, Polina Tsygankova, Denis Chistol, Konstantin Lyamzaev, Vyacheslav Tabakov, Svetlana Mikhaylova, Natalia Nikitina, Galina Rudenskaya, Aysylu Murtazina, Tatiana Markova, Natalia Semenova, Natalia Buchinskaya, Elena Saifullina, Hasyanya Aksyanova, Peter Sparber, Natalia Andreeva, Natalia Venediktova, Alina Ivanushkina, Daria Eliseeva, Yulia Murakhovskaya, Natalia Sheremet and Ekaterina Zakharovaadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2025, 26(10), 4565; https://doi.org/10.3390/ijms26104565 - 10 May 2025
Viewed by 644
Abstract
The m.13513G>A (p.Asp393Asn) substitution in the MT-ND5 (Mitochondrially Encoded NADH/Ubiquinone Oxidoreductase Core Subunit 5) gene is a common pathogenic variant associated with primary mitochondrial disorders. It frequently causes Leigh syndrome and mitochondrial encephalomyopathy with lactate acidosis and stroke-like episodes (MELAS). In this study, [...] Read more.
The m.13513G>A (p.Asp393Asn) substitution in the MT-ND5 (Mitochondrially Encoded NADH/Ubiquinone Oxidoreductase Core Subunit 5) gene is a common pathogenic variant associated with primary mitochondrial disorders. It frequently causes Leigh syndrome and mitochondrial encephalomyopathy with lactate acidosis and stroke-like episodes (MELAS). In this study, we present clinical data, heteroplasmy levels in various tissues (blood, urine, and skin fibroblasts), and bioenergetic characteristics from a cohort of 20 unrelated patients carrying the m.13513G>A mutation, classified according to the following phenotypes: Leigh syndrome (n = 12), MELAS (n = 2), and Leber’s hereditary optic neuropathy (LHON, n = 6). We observed a significant correlation between high respiratory ratios and heteroplasmy levels in fibroblast cell lines of the patients. Furthermore, fibroblast cell lines with heteroplasmy levels exceeding 55% exhibited markedly reduced mitochondrial membrane potential. These findings contribute to a better understanding of the clinical and bioenergetic profiles of patients with m.13513G>A-variant-related phenotypes across different heteroplasmy levels, based on data from a single genetic center. Our data suggest that even a slight shift in heteroplasmy can improve cellular function and, consequently, the patients’ phenotype, providing a solid foundation for the development of future gene therapies for mtDNA diseases. Full article
(This article belongs to the Special Issue The Impact of Mitochondria on Human Disease and Health)
Show Figures

Figure 1

18 pages, 2137 KiB  
Article
Complex Metabolomic Changes in a Combined Defect of Glycosylation and Oxidative Phosphorylation in a Patient with Pathogenic Variants in PGM1 and NDUFA13
by Silvia Radenkovic, Isabelle Adant, Matthew J. Bird, Johannes V. Swinnen, David Cassiman, Tamas Kozicz, Sarah C. Gruenert, Bart Ghesquière and Eva Morava
Cells 2025, 14(9), 638; https://doi.org/10.3390/cells14090638 - 25 Apr 2025
Viewed by 1207
Abstract
Inherited metabolic disorders (IMDs) are genetic disorders that occur in as many as 1:2500 births worldwide. Nevertheless, they are quite rare individually and even more rare is the co-occurrence of two IMDs in one individual. To better understand the metabolic cross-talk between glycosylation [...] Read more.
Inherited metabolic disorders (IMDs) are genetic disorders that occur in as many as 1:2500 births worldwide. Nevertheless, they are quite rare individually and even more rare is the co-occurrence of two IMDs in one individual. To better understand the metabolic cross-talk between glycosylation changes and deficient energy metabolism, and its potential effect on outcomes, we evaluated patient fibroblasts with likely pathogenic variants in PGM1 and pathogenic variants in NDUFA13 derived from a patient who passed away at 16 years of age. The patient presented with characteristic of PGM1-CDG including bifid uvula, muscle involvement, abnormal glycosylation in blood, and elevated liver transaminases. In addition, hearing loss, seizures, elevated plasma and CSF lactate and a Leigh-like MRI brain pattern were present, which are commonly associated with Leigh syndrome. PGM1-CDG has been reported in about 70 individuals, while NDUFA13 deficiency has so far only been reported in 13 patients. As abundant energy is essential for glycosylation, and both PGM1 and NDUFA13 are linked to energy metabolism, we sought to better understand the underlying biochemical cause of the patient’s clinical presentation. To do so, we performed extensive investigations including tracer metabolomics, lipidomics and enzymatic studies on the patient’s fibroblasts. We found a profound depletion of UDP-hexoses, consistent with PGM1-CDG. Complex I enzyme activity and mitochondrial function were also impaired, corroborating complex I deficiency and Leigh syndrome. Further, lipidomics analysis showed similarities with both PGM1-CDG and OXPHOS-deficient patients. Based on our results, the patient was diagnosed with both PGM1-CDG and Leigh syndrome. In summary, we present the first case of combined CDG and Leigh syndrome, caused by (likely) pathogenic variants in PGM1 and NDUFA13, and underline the importance of considering the synergistic effects of multiple disease-causing variants in patients with complex clinical presentation, leading to the patient’s early demise. Full article
Show Figures

Figure 1

27 pages, 666 KiB  
Review
Leigh Syndrome: A Comprehensive Review of the Disease and Present and Future Treatments
by Giuseppe Magro, Vincenzo Laterza and Federico Tosto
Biomedicines 2025, 13(3), 733; https://doi.org/10.3390/biomedicines13030733 - 17 Mar 2025
Cited by 2 | Viewed by 3844
Abstract
Leigh syndrome (LS) is a severe neurodegenerative condition with an early onset, typically during early childhood or infancy. The disorder exhibits substantial clinical and genetic diversity. From a clinical standpoint, Leigh syndrome showcases a broad range of irregularities, ranging from severe neurological issues [...] Read more.
Leigh syndrome (LS) is a severe neurodegenerative condition with an early onset, typically during early childhood or infancy. The disorder exhibits substantial clinical and genetic diversity. From a clinical standpoint, Leigh syndrome showcases a broad range of irregularities, ranging from severe neurological issues to minimal or no discernible abnormalities. The central nervous system is most affected, resulting in psychomotor retardation, seizures, nystagmus, ophthalmoparesis, optic atrophy, ataxia, dystonia, or respiratory failure. Some patients also experience involvement of the peripheral nervous system, such as polyneuropathy or myopathy, as well as non-neurological anomalies, such as diabetes, short stature, hypertrichosis, cardiomyopathy, anemia, renal failure, vomiting, or diarrhea (Leigh-like syndrome). Mutations associated with Leigh syndrome impact genes in both the mitochondrial and nuclear genomes. Presently, LS remains without a cure and shows limited response to various treatments, although certain case reports suggest potential improvement with supplements. Ongoing preclinical studies are actively exploring new treatment approaches. This review comprehensively outlines the genetic underpinnings of LS, its current treatment methods, and preclinical investigations, with a particular focus on treatment. Full article
(This article belongs to the Special Issue Progress in Neurodevelopmental Disorders Research)
Show Figures

Figure 1

18 pages, 288 KiB  
Review
Mitochondrial DNA Pathogenic Variants in Ophthalmic Diseases: A Review
by Khaled K. Abu-Amero, Bashaer Almadani, Shereen Abualkhair, Syed Hameed, Altaf A Kondkar, Andrea Sollazzo, Angeli Christy Yu, Massimo Busin and Giorgio Zauli
Genes 2025, 16(3), 347; https://doi.org/10.3390/genes16030347 - 17 Mar 2025
Viewed by 1300
Abstract
Mitochondria are vital organelles responsible for ATP production and metabolic regulation, essential for energy-intensive cells such as retinal ganglion cells. Dysfunction in mitochondrial oxidative phosphorylation or mitochondrial DNA (mtDNA) pathogenic variants can disrupt ATP synthesis, cause oxidative stress, and lead to cell death. [...] Read more.
Mitochondria are vital organelles responsible for ATP production and metabolic regulation, essential for energy-intensive cells such as retinal ganglion cells. Dysfunction in mitochondrial oxidative phosphorylation or mitochondrial DNA (mtDNA) pathogenic variants can disrupt ATP synthesis, cause oxidative stress, and lead to cell death. This has profound implications for tissues such as the retina, optic nerve, and retinal pigment epithelium, which are dependent on robust mitochondrial function. In this review, we provide a comprehensive compilation of pathogenic variants in the mtDNA associated with various ophthalmic diseases, including Leber’s hereditary optic neuropathy, chronic progressive external ophthalmoplegia, Leigh syndrome, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes, among others. We highlight the genetic variants implicated in these conditions, their pathogenic roles, and the phenotypic consequences of mitochondrial dysfunction in ocular tissues. In addition to well-established mutations, we also discuss the emerging evidence of the role of mtDNA’s variants in complex multifactorial diseases, such as non-arteritic anterior ischemic optic neuropathy, primary open-angle glaucoma, and age-related macular degeneration. The review aims to serve as a valuable resource for clinicians and researchers, providing a detailed overview of mtDNA pathogenic variants and their clinical significance in the context of mitochondrial-related eye diseases. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
14 pages, 2421 KiB  
Case Report
Adult Leigh Syndrome Associated with the m.15635T>C Mitochondrial DNA Variant Affecting the Cytochrome b (MT-CYB) Gene
by Concetta Valentina Tropeano, Chiara La Morgia, Alessandro Achilli, Luisa Iommarini, Gaia Tioli, Leonardo Caporali, Anna Olivieri, Maria Lucia Valentino, Rocco Liguori, Piero Barboni, Andrea Martinuzzi, Caterina Tonon, Raffaele Lodi, Antonio Torroni, Valerio Carelli and Anna Maria Ghelli
Int. J. Mol. Sci. 2025, 26(3), 1116; https://doi.org/10.3390/ijms26031116 - 27 Jan 2025
Viewed by 1090
Abstract
We report on a sporadic patient suffering Leigh syndrome characterized by bilateral lesions in the lenticular nuclei and spastic dystonia, intellectual disability, sensorineural deafness, hypertrophic cardiomyopathy, exercise intolerance, and retinitis pigmentosa. Complete sequencing of mitochondrial DNA revealed the heteroplasmic nucleotide change m.15635T>C affecting [...] Read more.
We report on a sporadic patient suffering Leigh syndrome characterized by bilateral lesions in the lenticular nuclei and spastic dystonia, intellectual disability, sensorineural deafness, hypertrophic cardiomyopathy, exercise intolerance, and retinitis pigmentosa. Complete sequencing of mitochondrial DNA revealed the heteroplasmic nucleotide change m.15635T>C affecting a highly conserved amino acid position (p.Ser297Pro) in the cytochrome b (MT-CYB) gene on a haplogroup K1c1a background, which includes a set of four non-synonymous polymorphisms also present in the same gene. Biochemical studies documented respiratory chain impairment due to complex III defect. This variant fulfils the criteria for being pathogenic and was previously reported in a sporadic case of fatal neonatal polyvisceral failure. Full article
(This article belongs to the Special Issue Mitochondrial Biology and Human Diseases)
Show Figures

Figure 1

16 pages, 1148 KiB  
Article
NADH Reductive Stress and Its Correlation with Disease Severity in Leigh Syndrome: A Pilot Study Using Patient Fibroblasts and a Mouse Model
by Tamaki Ishima, Natsuka Kimura, Mizuki Kobayashi, Chika Watanabe, Eriko F. Jimbo, Ryosuke Kobayashi, Takuro Horii, Izuho Hatada, Kei Murayama, Akira Ohtake, Ryozo Nagai, Hitoshi Osaka and Kenichi Aizawa
Biomolecules 2025, 15(1), 38; https://doi.org/10.3390/biom15010038 - 31 Dec 2024
Cited by 1 | Viewed by 1779
Abstract
Nicotinamide adenine dinucleotide (NAD) is a critical cofactor in mitochondrial energy production. The NADH/NAD+ ratio, reflecting the balance between NADH (reduced) and NAD+ (oxidized), is a key marker for the severity of mitochondrial diseases. We recently developed a [...] Read more.
Nicotinamide adenine dinucleotide (NAD) is a critical cofactor in mitochondrial energy production. The NADH/NAD+ ratio, reflecting the balance between NADH (reduced) and NAD+ (oxidized), is a key marker for the severity of mitochondrial diseases. We recently developed a streamlined LC-MS/MS method for the precise measurement of NADH and NAD+. Utilizing this technique, we quantified NADH and NAD+ levels in fibroblasts derived from pediatric patients and in a Leigh syndrome mouse model in which mitochondrial respiratory chain complex I subunit Ndufs4 is knocked out (KO). In patient-derived fibroblasts, NAD+ levels did not differ significantly from those of healthy controls (p = 0.79); however, NADH levels were significantly elevated (p = 0.04), indicating increased NADH reductive stress. This increase, observed despite comparable total NAD(H) levels between the groups, was attributed to elevated NADH levels. Similarly, in the mouse model, NADH levels were significantly increased in the KO group (p = 0.002), further suggesting that NADH elevation drives reductive stress. This precise method for NADH measurement is expected to outperform conventional assays, such as those for lactate, providing a simpler and more reliable means of assessing disease progression. Full article
(This article belongs to the Special Issue NAD Metabolism in Physiology and Pathology)
Show Figures

Figure 1

9 pages, 591 KiB  
Commentary
LNC-ing Genetics in Mitochondrial Disease
by Rick Kamps and Emma Louise Robinson
Non-Coding RNA 2024, 10(6), 57; https://doi.org/10.3390/ncrna10060057 - 15 Nov 2024
Viewed by 1691
Abstract
Primary mitochondrial disease (MD) is a group of rare genetic diseases reported to have a prevalence of 1:5000 and is currently without a cure. This group of diseases includes mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), maternally inherited diabetes and deafness (MIDD), [...] Read more.
Primary mitochondrial disease (MD) is a group of rare genetic diseases reported to have a prevalence of 1:5000 and is currently without a cure. This group of diseases includes mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), maternally inherited diabetes and deafness (MIDD), Leber’s hereditary optic neuropathy (LHON), Leigh syndrome (LS), Kearns–Sayre syndrome (KSS), and myoclonic epilepsy and ragged-red fiber disease (MERRF). Additionally, secondary mitochondrial dysfunction has been implicated in the most common current causes of mortality and morbidity, including cardiovascular disease (CVD) and cancer. Identifying key genetic contributors to both MD and secondary mitochondrial dysfunction may guide clinicians to assess the most effective treatment course and prognosis, as well as informing family members of any hereditary risk of disease transmission. Identifying underlying genetic causes of primary and secondary MD involves either genome sequencing (GS) or small targeted panel analysis of known disease-causing nuclear- or mitochondrial genes coding for mitochondria-related proteins. Due to advances in GS, the importance of long non-coding RNA (lncRNA) as functional contributors to the pathophysiology of MD is being unveiled. A limited number of studies have thus far reported the importance of lncRNAs in relation to MD causation and progression, and we are entering a new area of attention for clinical geneticists in specific rare malignancies. This commentary provides an overview of what is known about the role of lncRNAs as genetic and molecular contributors to disease pathophysiology and highlights an unmet need for a deeper understanding of mitochondrial dysfunction in serious human disease burdens. Full article
Show Figures

Figure 1

11 pages, 1429 KiB  
Guidelines
A Comprehensive Approach to the Diagnosis of Leigh Syndrome Spectrum
by Manuela Schubert Baldo, Luísa Azevedo, Margarida Paiva Coelho, Esmeralda Martins and Laura Vilarinho
Diagnostics 2024, 14(19), 2133; https://doi.org/10.3390/diagnostics14192133 - 25 Sep 2024
Cited by 1 | Viewed by 2420
Abstract
Background: Leigh syndrome spectrum (LSS) is a novel nomenclature that encompasses both classical Leigh syndrome and Leigh-like phenotypes. Given the heterogeneity of disease presentation, a new consensus published recently addressed the main issues and proposed general guidelines towards diagnosis. Based on these recommendations, [...] Read more.
Background: Leigh syndrome spectrum (LSS) is a novel nomenclature that encompasses both classical Leigh syndrome and Leigh-like phenotypes. Given the heterogeneity of disease presentation, a new consensus published recently addressed the main issues and proposed general guidelines towards diagnosis. Based on these recommendations, we developed a simple pipeline that can be useful in the diagnosis of LSS. Methods: We combined previously published criteria with our own experience to achieve a diagnostic framework that can provide faster satisfactory results with fewer resources. Results: We suggest adding basic biochemical tests for amino acids, acylcarnitine, and urinary organic acids as parallel investigations, as these results can be obtained in a short time. This approach characterized 80% of our cohort and promoted specific intervention in 10% of confirmed cases. Conclusions: Genetic studies are crucial in the diagnosis of LSS, but they are time-consuming and might delay tailored interventions. Therefore, we suggest adding more affordable and less complex biochemical studies as primary tests when investigating treatable causes of LSS. Full article
(This article belongs to the Section Pathology and Molecular Diagnostics)
Show Figures

Figure 1

18 pages, 1415 KiB  
Review
New Insights into Mitochondria in Health and Diseases
by Ya Li, Huhu Zhang, Chunjuan Yu, Xiaolei Dong, Fanghao Yang, Mengjun Wang, Ziyuan Wen, Mohan Su, Bing Li and Lina Yang
Int. J. Mol. Sci. 2024, 25(18), 9975; https://doi.org/10.3390/ijms25189975 - 16 Sep 2024
Cited by 16 | Viewed by 8618
Abstract
Mitochondria are a unique type of semi-autonomous organelle within the cell that carry out essential functions crucial for the cell’s survival and well-being. They are the location where eukaryotic cells carry out energy metabolism. Aside from producing the majority of ATP through oxidative [...] Read more.
Mitochondria are a unique type of semi-autonomous organelle within the cell that carry out essential functions crucial for the cell’s survival and well-being. They are the location where eukaryotic cells carry out energy metabolism. Aside from producing the majority of ATP through oxidative phosphorylation, which provides essential energy for cellular functions, mitochondria also participate in other metabolic processes within the cell, such as the electron transport chain, citric acid cycle, and β-oxidation of fatty acids. Furthermore, mitochondria regulate the production and elimination of ROS, the synthesis of nucleotides and amino acids, the balance of calcium ions, and the process of cell death. Therefore, it is widely accepted that mitochondrial dysfunction is a factor that causes or contributes to the development and advancement of various diseases. These include common systemic diseases, such as aging, diabetes, Parkinson’s disease, and cancer, as well as rare metabolic disorders, like Kearns–Sayre syndrome, Leigh disease, and mitochondrial myopathy. This overview outlines the various mechanisms by which mitochondria are involved in numerous illnesses and cellular physiological activities. Additionally, it provides new discoveries regarding the involvement of mitochondria in both disorders and the maintenance of good health. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
Show Figures

Figure 1

15 pages, 2057 KiB  
Review
Mechanisms and Future Research Perspectives on Mitochondrial Diseases Associated with Isoleucyl-tRNA Synthetase Gene Mutations
by Masaki Watanabe and Nobuya Sasaki
Genes 2024, 15(7), 894; https://doi.org/10.3390/genes15070894 - 8 Jul 2024
Cited by 1 | Viewed by 2515
Abstract
Aminoacyl-tRNA synthetases are essential enzymes for the accurate translation of genetic information. IARS1 and IARS2 are isoleucyl-tRNA synthetases functioning in the cytoplasm and mitochondria, respectively, with genetic mutations in these enzymes causing diverse clinical phenotypes in specific organs and tissues. Mutations in IARS1 [...] Read more.
Aminoacyl-tRNA synthetases are essential enzymes for the accurate translation of genetic information. IARS1 and IARS2 are isoleucyl-tRNA synthetases functioning in the cytoplasm and mitochondria, respectively, with genetic mutations in these enzymes causing diverse clinical phenotypes in specific organs and tissues. Mutations in IARS1 and IARS2 have recently been linked to mitochondrial diseases. This review aims to explore the relationship between IARS1 and IARS2 and these diseases, providing a comprehensive overview of their association with mitochondrial diseases. Mutations in IARS1 cause weak calf syndrome in cattle and mitochondrial diseases in humans, leading to growth retardation and liver dysfunction. Mutations in IARS2 are associated with Leigh syndrome, craniosynostosis and abnormal genitalia syndrome. Future research is expected to involve genetic analysis of a larger number of patients, identifying new mutations in IARS1 and IARS2, and elucidating their impact on mitochondrial function. Additionally, genetically modified mice and the corresponding phenotypic analysis will serve as powerful tools for understanding the functions of these gene products and unraveling disease mechanisms. This will likely promote the development of new therapies and preventive measures. Full article
Show Figures

Figure 1

7 pages, 3022 KiB  
Case Report
New Case of Spinocerebellar Ataxia, Autosomal Recessive 4, Due to VPS13D Variants
by Denis Kistol, Polina Tsygankova, Fatima Bostanova, Maria Orlova and Ekaterina Zakharova
Int. J. Mol. Sci. 2024, 25(10), 5127; https://doi.org/10.3390/ijms25105127 - 8 May 2024
Cited by 1 | Viewed by 2768
Abstract
Movement disorders such as bradykinesia, tremor, dystonia, chorea, and myoclonus most often arise in several neurodegenerative diseases with basal ganglia and white matter involvement. While the pathophysiology of these disorders remains incompletely understood, dysfunction of the basal ganglia and related brain regions is [...] Read more.
Movement disorders such as bradykinesia, tremor, dystonia, chorea, and myoclonus most often arise in several neurodegenerative diseases with basal ganglia and white matter involvement. While the pathophysiology of these disorders remains incompletely understood, dysfunction of the basal ganglia and related brain regions is often implicated. The VPS13D gene, part of the VPS13 family, has emerged as a crucial player in neurological pathology, implicated in diverse phenotypes ranging from movement disorders to Leigh syndrome. We present a clinical case of VPS13D-associated disease with two variants in the VPS13D gene in an adult female. This case contributes to our evolving understanding of VPS13D-related diseases and underscores the importance of genetic screening in diagnosing and managing such conditions. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
Show Figures

Figure 1

15 pages, 1932 KiB  
Article
The Blood–Brain Barrier Is Unaffected in the Ndufs4−/− Mouse Model of Leigh Syndrome
by Robin Reynaud-Dulaurier, Romain Clément, Sara Yjjou, Cassandra Cresson, Yasmina Saoudi, Mathilde Faideau and Michael Decressac
Int. J. Mol. Sci. 2024, 25(9), 4828; https://doi.org/10.3390/ijms25094828 - 29 Apr 2024
Viewed by 2262
Abstract
Mitochondrial dysfunction plays a major role in physiological aging and in many pathological conditions. Yet, no study has explored the consequence of primary mitochondrial deficiency on the blood–brain barrier (BBB) structure and function. Addressing this question has major implications for pharmacological and genetic [...] Read more.
Mitochondrial dysfunction plays a major role in physiological aging and in many pathological conditions. Yet, no study has explored the consequence of primary mitochondrial deficiency on the blood–brain barrier (BBB) structure and function. Addressing this question has major implications for pharmacological and genetic strategies aimed at ameliorating the neurological symptoms that are often predominant in patients suffering from these conditions. In this study, we examined the permeability of the BBB in the Ndufs4−/− mouse model of Leigh syndrome (LS). Our results indicated that the structural and functional integrity of the BBB was preserved in this severe model of mitochondrial disease. Our findings suggests that pharmacological or gene therapy strategies targeting the central nervous system in this mouse model and possibly other models of mitochondrial dysfunction require the use of specific tools to bypass the BBB. In addition, they raise the need for testing the integrity of the BBB in complementary in vivo models. Full article
(This article belongs to the Special Issue Blood-Brain Barrier in Neuroinflammation and Neurological Diseases)
Show Figures

Figure 1

10 pages, 1544 KiB  
Article
Biallelic NDUFA4 Deletion Causes Mitochondrial Complex IV Deficiency in a Patient with Leigh Syndrome
by Doriana Misceo, Petter Strømme, Fatemeh Bitarafan, Maninder Singh Chawla, Ying Sheng, Sandra Monica Bach de Courtade, Lars Eide and Eirik Frengen
Genes 2024, 15(4), 500; https://doi.org/10.3390/genes15040500 - 17 Apr 2024
Cited by 6 | Viewed by 2648
Abstract
Oxidative phosphorylation involves a complex multi-enzymatic mitochondrial machinery critical for proper functioning of the cell, and defects herein cause a wide range of diseases called “primary mitochondrial disorders” (PMDs). Mutations in about 400 nuclear and 37 mitochondrial genes have been documented to cause [...] Read more.
Oxidative phosphorylation involves a complex multi-enzymatic mitochondrial machinery critical for proper functioning of the cell, and defects herein cause a wide range of diseases called “primary mitochondrial disorders” (PMDs). Mutations in about 400 nuclear and 37 mitochondrial genes have been documented to cause PMDs, which have an estimated birth prevalence of 1:5000. Here, we describe a 4-year-old female presenting from early childhood with psychomotor delay and white matter signal changes affecting several brain regions, including the brainstem, in addition to lactic and phytanic acidosis, compatible with Leigh syndrome, a genetically heterogeneous subgroup of PMDs. Whole genome sequencing of the family trio identified a homozygous 12.9 Kb deletion, entirely overlapping the NDUFA4 gene. Sanger sequencing of the breakpoints revealed that the genomic rearrangement was likely triggered by Alu elements flanking the gene. NDUFA4 encodes for a subunit of the respiratory chain Complex IV, whose activity was significantly reduced in the patient’s fibroblasts. In one family, dysfunction of NDUFA4 was previously documented as causing mitochondrial Complex IV deficiency nuclear type 21 (MC4DN21, OMIM 619065), a relatively mild form of Leigh syndrome. Our finding confirms the loss of NDUFA4 function as an ultra-rare cause of Complex IV defect, clinically presenting as Leigh syndrome. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
Show Figures

Figure 1

9 pages, 1586 KiB  
Article
Expansion of Electron Transport Chain Mutants That Cause Anesthetic-Induced Toxicity in Drosophila melanogaster
by Luke A. Borchardt, Zachariah P. G. Olufs, Philip G. Morgan, David A. Wassarman and Misha Perouansky
Oxygen 2024, 4(1), 108-116; https://doi.org/10.3390/oxygen4010006 - 2 Mar 2024
Cited by 1 | Viewed by 1254
Abstract
The mitochondrial electron transport chain (mETC) contains molecular targets of volatile general anesthetics (VGAs), which places individuals with mETC mutations at risk for anesthetic complications, as exemplified by patients with Leigh syndrome (LS). The Drosophila melanogaster homozygous mutant for ND-23, which encodes [...] Read more.
The mitochondrial electron transport chain (mETC) contains molecular targets of volatile general anesthetics (VGAs), which places individuals with mETC mutations at risk for anesthetic complications, as exemplified by patients with Leigh syndrome (LS). The Drosophila melanogaster homozygous mutant for ND-23, which encodes a subunit of mETC Complex I, replicates numerous characteristics of LS, including neurodegeneration, shortened lifespan, behavioral anesthetic hypersensitivity, and toxicity. The anesthetic phenotype of toxicity (lethality) is also observed in flies homozygous for mutations in other Complex I subunits. By contrast, mutations conferring sensitivity have not yet been identified for subunits of Complexes II–V. Furthermore, anesthetic phenotypes are thought to be recessive; that is, risk is not conferred by heterozygous mutations. However, at older ages, exposure of heterozygous mutant ND-23 flies to the VGA isoflurane in 75% oxygen (hyperoxia) results in toxicity. It is also unknown whether combinations of heterozygous mutations in different subunits of the mETC can result in anesthetic toxicity. Here, we show that, following exposure to isoflurane in hyperoxia, flies carrying heterozygous mutations in two Complex I subunits, ND-23 and ND-SGDH (NADH dehydrogenase (ubiquinone) SGDH subunit), had a level of anesthetic toxicity that exceeded the added toxicities of the individual heterozygous mutations. In addition, we show that flies heterozygous for two different alleles of the Complex II gene SdhB were susceptible to isoflurane/hyperoxia-induced anesthetic toxicity. Finally, a mutation in the SdhC subunit of Complex II of Caenorhabditis elegans resulted in isoflurane-induced mortality, supporting the role of Complex II in anesthetic toxicity. These data expand the landscape of mutations in the mETC that increase sensitivity to anesthetic toxicity. Full article
(This article belongs to the Special Issue Mitochondrial Oxidative Stress in Health and Disease)
Show Figures

Figure 1

Back to TopTop