bims-curels 2024-09-29 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2024–09–29
eleven papers selected by
Cure Mito Foundation

Primary mitochondrial diseases.
Emerging Multi-omic Approaches to the Molecular Diagnosis of Mitochondrial Disease and Available Strategies for Treatment and Prevention.
Fetal and obstetrics manifestations of mitochondrial diseases.
Leigh has no Brakes: Impaired Inhibition in a Mouse Model of Leigh Syndrome Leads to Enhanced Seizure Sensitivity.
Interferon Stimulated Gene Expression Is a Biomarker for Primary Mitochondrial Disease.
Beyond MitoCarta-expanding the list of candidate proteins involved in mitochondrial functions using a biological network approach.
Ndufs4 inactivation in glutamatergic neurons reveals swallow-breathing discoordination in a mouse model of Leigh Syndrome.
Cochlear Implantation for Isoleucyl-tRNA Synthetase Mutation-Associated Mitochondrial Disease: A Case Report.
Retinal damage promotes mitochondrial transfer in the visual system of a mouse model of Leber hereditary optic neuropathy.
Riding the gene therapy wave: challenges and opportunities for rare disease patients and clinicians.
Bi-Allelic Splicing Variant, c.153-2A > C in TOMM7 Is Associated With Leigh Syndrome.

Handb Clin Neurol. 2024 ;pii: B978-0-323-99209-1.00004-1. [Epub ahead of print]204 53-76

Primary mitochondrial diseases.

Chiara Pizzamiglio, Michael G Hanna, Robert D S Pitceathly.

  Primary mitochondrial diseases (PMDs) are a heterogeneous group of hereditary disorders characterized by an impairment of the mitochondrial respiratory chain. They are the most common group of genetic metabolic disorders, with a prevalence of 1 in 4,300 people. The presence of leukoencephalopathy is recognized as an important feature in many PMDs and can be a manifestation of mutations in both mitochondrial DNA (classic syndromes such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; myoclonic epilepsy with ragged-red fibers [RRFs]; Leigh syndrome; and Kearns-Sayre syndrome) and nuclear DNA (mutations in maintenance genes such as POLG, MPV17, and TYMP; Leigh syndrome; and mitochondrial aminoacyl-tRNA synthetase disorders). In this chapter, PMDs associated with white matter involvement are outlined, including details of clinical presentations, brain MRI features, and elements of differential diagnoses. The current approach to the diagnosis of PMDs and management strategies are also discussed. A PMD diagnosis in a subject with leukoencephalopathy should be considered in the presence of specific brain MRI features (for example, cyst-like lesions, bilateral basal ganglia lesions, and involvement of both cerebral hemispheres and cerebellum), in addition to a complex neurologic or multisystem disorder. Establishing a genetic diagnosis is crucial to ensure appropriate genetic counseling, multidisciplinary team input, and eligibility for clinical trials.

Keywords:  Brain MRI; Kearns-Sayre syndrome; Leber hereditary optic neuropathy; Leigh disease; Leukoencephalopathy; Mitochondrial DNA maintenance disorders; Mitochondrial aminoacyl-tRNA synthetase disorders; Mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes; Mitochondrial neurogastrointestinal encephalomyopathy; Primary mitochondrial diseases

DOI:  https://doi.org/10.1016/B978-0-323-99209-1.00004-1
Curr Genomics. 2024 ;25(5): 358-379

Emerging Multi-omic Approaches to the Molecular Diagnosis of Mitochondrial Disease and Available Strategies for Treatment and Prevention.

Faeze Khaghani, Mahboobeh Hemmati, Masoumeh Ebrahimi, Arash Salmaninejad.

  Mitochondria are semi-autonomous organelles present in several copies within most cells in the human body that are controlled by the precise collaboration of mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) encoding mitochondrial proteins. They play important roles in numerous metabolic pathways, such as the synthesis of adenosine triphosphate (ATP), the predominant energy substrate of the cell generated through oxidative phosphorylation (OXPHOS), intracellular calcium homeostasis, metabolite biosynthesis, aging, cell cycles, and so forth. Previous studies revealed that dysfunction of these multi-functional organelles, which may arise due to mutations in either the nuclear or mitochondrial genome, leads to a diverse group of clinically and genetically heterogeneous disorders. These diseases include neurodegenerative and metabolic disorders as well as cardiac and skeletal myopathies in both adults and newborns. The plethora of phenotypes and defects displayed leads to challenges in the diagnosis and treatment of mitochondrial diseases. In this regard, the related literature proposed several diagnostic options, such as high throughput mitochondrial genomics and omics technologies, as well as numerous therapeutic options, such as pharmacological approaches, manipulating the mitochondrial genome, increasing the mitochondria content of the affected cells, and recently mitochondrial diseases transmission prevention. Therefore, the present article attempted to review the latest advances and challenges in diagnostic and therapeutic options for mitochondrial diseases.

Keywords:  Mitochondrial disease; genomic; metabolomics; omics; proteomics; transcriptomics

DOI:  https://doi.org/10.2174/0113892029308327240612110334
J Transl Med. 2024 Sep 23. 22(1): 853

Fetal and obstetrics manifestations of mitochondrial diseases.

Adelizzi Alessia, Giri Anastasia, Di Donfrancesco Alessia, Boito Simona, Prigione Alessandro, Bottani Emanuela, Bollati Valentina, Tiranti Valeria, Persico Nicola, Brunetti Dario.

During embryonic and neonatal development, mitochondria have essential effects on metabolic and energetic regulation, shaping cell fate decisions and leading to significant short- and long-term effects on embryonic and offspring health. Therefore, perturbation on mitochondrial function can have a pathological effect on pregnancy. Several shreds of evidence collected in preclinical models revealed that severe mitochondrial dysfunction is incompatible with life or leads to critical developmental defects, highlighting the importance of correct mitochondrial function during embryo-fetal development. The mechanism impairing the correct development is unknown and may include a dysfunctional metabolic switch in differentiating cells due to decreased ATP production or altered apoptotic signalling. Given the central role of mitochondria in embryonic and fetal development, the mitochondrial dysfunction typical of Mitochondrial Diseases (MDs) should, in principle, be detectable during pregnancy. However, little is known about the clinical manifestations of MDs in embryonic and fetal development. In this manuscript, we review preclinical and clinical evidence suggesting that MDs may affect fetal development and highlight the fetal and maternal outcomes that may provide a wake-up call for targeted genetic diagnosis.

DOI: https://doi.org/10.1186/s12967-024-05633-6
Epilepsy Curr. 2024 Jul-Aug;24(4):24(4): 298-300

Leigh has no Brakes: Impaired Inhibition in a Mouse Model of Leigh Syndrome Leads to Enhanced Seizure Sensitivity.

Gordon F Buchanan.

DOI: https://doi.org/10.1177/15357597241257031
Ann Neurol. 2024 Sep 25.

Interferon Stimulated Gene Expression Is a Biomarker for Primary Mitochondrial Disease.

Nandaki Keshavan, Lana Mhaldien, Kimberly Gilmour, Shamima Rahman.

OBJECTIVE: Mitochondria are implicated in regulation of the innate immune response. We hypothesized that abnormalities in interferon signaling may contribute to pathophysiology in patients with primary mitochondrial disease (PMD).
METHODS: Expression of interferon stimulated genes (ISGs) was measured by real-time polymerase chain reaction (PCR) in whole blood samples from a cohort of patients with PMD.
RESULTS: Upregulated ISG expression was observed in a high proportion (41/55, 75%) of patients with PMD on at least 1 occasion, most frequently IFI27 upregulation, seen in 50% of the samples. Some patients had extremely high IFI27 levels, similar to those seen in patients with primary interferonopathies. A statistically significant correlation was observed between elevated IFI27 gene expression and PMD, but not between IFI27 and secondary mitochondrial dysfunction, suggesting that ISG upregulation is a biomarker of PMD. In some patients with PMD, ISG abnormalities persisted on repeat measurement over several years, indicative of ongoing chronic inflammation. Subgroup analyses suggested common ISG signatures in patients with similar mitochondrial disease mechanisms and positive correlations with disease severity among patients with identical genetic diagnoses.
INTERPRETATION: Dysregulated interferon signaling is frequently seen in patients with PMD suggesting that interferon dysregulation is a contributor to pathophysiology. This may indicate a role for repurposing of immunomodulatory therapies for the treatment of PMDs by targeting interferon signaling. ANN NEUROL 2024.

DOI: https://doi.org/10.1002/ana.27081
NAR Genom Bioinform. 2023 Dec;5(4): lqad107

Beyond MitoCarta-expanding the list of candidate proteins involved in mitochondrial functions using a biological network approach.

Dmitriy Leyfer, Jessica L Fetterman.

Mitochondrial diseases are the result of pathogenic variants in genes involved in the diverse functions of the mitochondrion. A comprehensive list of mitochondrial genes is needed to improve gene prioritization in the diagnosis of mitochondrial diseases and development of therapeutics that modulate mitochondrial function. MitoCarta is an experimentally derived catalog of proteins localized to mitochondria. We sought to expand this list of mitochondrial proteins to identify proteins that may not be localized to the mitochondria yet perform important mitochondrial functions. We used a computational approach to assign statistical significance to the overlap between STRING database gene network neighborhoods and MitoCarta proteins. Using a data-driven stringent significance threshold, 2059 proteins that were not located in MitoCarta were identified, which we termed mitochondrial proximal (MitoProximal) proteins. We identified all of the oxidative phosphorylation complex subunits and 90% of 149 genes that contain confirmed oxidative phosphorylation disease causal variants, lending validation to our methodology. Among the MitoProximal proteins, 134 are annotated to be localized to mitochondria but are not in the MitoCarta 3.0 database. We extend MitoCarta nearly 3-fold, generating a more comprehensive list of mitochondrial genes, a resource to facilitate the identification of pathogenic variants in mitochondrial and metabolic diseases.

DOI: https://doi.org/10.1093/nargab/lqad107
bioRxiv. 2024 Sep 15. pii: 2024.09.11.612506. [Epub ahead of print]

Ndufs4 inactivation in glutamatergic neurons reveals swallow-breathing discoordination in a mouse model of Leigh Syndrome.

Alyssa Huff, Luiz Marcelo Oliveira, Marlusa Karlen-Amarante, Favour Ebiala, Jan Marino Ramirez, Franck Kalume.

Swallowing, both nutritive and non-nutritive, is highly dysfunctional in children with Leigh Syndrome (LS) and contributes to the need for both gastrostomy and tracheostomy tube placement. Without these interventions aspiration of food, liquid, and mucus occur resulting in repeated bouts of respiratory infection. No study has investigated whether mouse models of LS, a neurometabolic disorder, exhibit dysfunctions in neuromuscular activity of swallow and breathing integration. We used a genetic mouse model of LS in which the NDUFS4 gene is knocked out (KO) specifically in Vglut2 or Gad2 neurons. We found increased variability of the swallow motor pattern, disruption in breathing regeneration post swallow, and water-induced apneas only in Vglut2 KO mice. These physiological changes likely contribute to weight loss and premature death seen in this mouse model. Following chronic hypoxia (CH) exposure, swallow motor pattern, breathing regeneration, weight, and life expectancy were not changed in the Vglut2-Ndufs4-KO CH mice compared to control, indicating a rescue of phenotypes. These findings show that like patients with LS, Ndufs4 mouse models of LS exhibit swallow impairments as well as swallow-breathing dyscoordination alongside the other phenotypic traits described in previous studies. Understanding this aspect of LS will open roads for the development of future more efficacious therapeutic intervention for this illness.

DOI: https://doi.org/10.1101/2024.09.11.612506
Cureus. 2024 Aug;16(8): e67760

Cochlear Implantation for Isoleucyl-tRNA Synthetase Mutation-Associated Mitochondrial Disease: A Case Report.

Masaomi Motegi, Yuika Sakurai, Yasushi Mio, Toya Ohashi.

  Biallelic missense mutations in the nuclear-encoded, cytosolic isoleucyl-tRNA synthetase (IARS) gene are associated with a rare and complex multisystemic phenotype, including growth retardation, intellectual disability, muscular hypotonia, diabetes mellitus, and deafness. These mutations impact the cytosolic isoform of IARS, which plays a crucial role in protein synthesis. The pathogenesis involves mitochondrial dysfunction, despite IARS being primarily a cytosolic enzyme, potentially linking it to the observed clinical manifestations. The efficacy of cochlear implantation for deafness due to IARS mutations and the safety of general anesthesia in such patients remain unclear. This report describes a rare case of progressive sensorineural hearing loss caused by IARS mutation-associated mitochondrial disease, which was successfully treated with cochlear implantation. Additionally, we discuss the safety of general anesthesia in this patient. A Japanese woman with IARS mutation-associated mitochondrial disease was diagnosed with severe bilateral sensorineural hearing loss at five years of age and immediately received hearing aids. Her hearing progressively deteriorated to profound impairment, necessitating cochlear implantation at 26 years of age, which resulted in satisfactory hearing. Furthermore, no perioperative general anesthesia-related adverse events were reported. Our case demonstrates that cochlear implantation can effectively restore hearing. This suggests that sensorineural hearing loss caused by IARS deficiency is primarily due to cochlear dysfunction. This case demonstrated that hearing loss is a crucial feature of IARS mutation-associated mitochondrial disease, which can be mitigated by cochlear implantation. While general anesthesia can be safely administered, careful consideration of anesthetic choices, such as avoiding depolarizing muscle relaxants and prolonged use of propofol, is essential to prevent complications. In this case, general anesthesia was well tolerated without perioperative events, providing valuable insight into the potential safety of such procedures in similar patients. Nevertheless, further studies are needed to confirm these findings across a broader population.

Keywords:  anesthesia complication; cochlear implantation; diabetes mellitus; general anesthesia; intellectual disability; iras mutation; mitochondrial disease; profound sensorineural hearing loss

DOI:  https://doi.org/10.7759/cureus.67760
Neurobiol Dis. 2024 Sep 25. pii: S0969-9961(24)00281-X. [Epub ahead of print] 106681

Retinal damage promotes mitochondrial transfer in the visual system of a mouse model of Leber hereditary optic neuropathy.

Pascal Ezan, Eléonore Hardy, Alexis Bemelmans, Magali Taiel, Elena Dossi, Nathalie Rouach.

  Lenadogene nolparvovec is a gene therapy which has been developed to treat Leber hereditary optic neuropathy (LHON) caused by a point mutation in the mitochondrial NADH dehydrogenase 4 (ND4) gene. Clinical trials have demonstrated a significant improvement of visual acuity up to 5 years after treatment by lenadogene nolparvovec but, surprisingly, unilateral treatment resulted in bilateral improvement of vision. This contralateral effect - similarly observed with other gene therapy products in development for MT-ND4-LHON - is supported by the migration of viral vector genomes and their transcripts to the contralateral eye, as reported in animals, and post-mortem samples from two patients. In this study, we used an AAV2 encoding fluorescent proteins targeting mitochondria to investigate whether these organelles themselves could transfer from the treated eye to the fellow one. We found that mitochondria travel along the visual system (optic chiasm and primary visual cortex) and reach the contralateral eye (optic nerve and retina) in physiological conditions. We also observed that, in a rotenone-induced model of retinal damage mimicking LHON, mitochondrial transfer from the healthy to the damaged eye was accelerated and enhanced. Our results thus provide a further explanation for the contralateral beneficial effect observed during clinical studies with lenadogene nolparvovec.

Keywords:  Gene therapy; Leber hereditary optic neuropathy; Mitochondrial transfer; Optic nerve; Retina; Viral vector

DOI:  https://doi.org/10.1016/j.nbd.2024.106681
Curr Opin Pediatr. 2024 Sep 18.

Riding the gene therapy wave: challenges and opportunities for rare disease patients and clinicians.

Matthew S Alexander, Nathaniel H Robin.

PURPOSE OF REVIEW: A growing number of gene therapies are getting FDA-approved for pediatric rare disorders to treat once incurable diseases. Opportunities for preventing lifetime illness and improving quality of life for these patients is now becoming a reality. Challenges exist in navigating the complexities of determining which patients will benefit from these new gene therapies and how to effectively deliver them as a standard of care.
RECENT FINDINGS: Gene therapies have been approved for pediatric hematological, neuromuscular, cancer, and other disorders that have improved the quality of life for rare disease patients. FDA approval of these drugs has been on a case-by-case basis leading towards gaps in drug approval, physician and patient knowledge of new gene therapies, and ultimate delivery of these drugs. Identifying patients that would benefit from these drugs and other coordination of care issues have arisen with each unique gene therapy product. These gene therapies have unique requirements and patient indications that require a knowledgeable group of physicians and hospital administrators to incorporate their use as a standard of care. With more gene therapies on the near horizon for FDA approval, multidisciplinary teams may improve patient access to these drugs by streamlining approaches towards adapting gene therapies into clinical use.
SUMMARY: The rapid increase in the number of FDA-approved gene therapies has not only created a number of challenges but also opportunities to improve the lives of pediatric patients with rare disorders. The adaptability of physicians, hospitals, and governmental regulatory boards is essential for delivering these new gene therapies safely and efficiently to these rare disease patients. Challenges still remain as to future requirements for additional gene therapy dosing and how to best manage financial burdens placed on the patient and providing institution.

DOI: https://doi.org/10.1097/MOP.0000000000001402
Am J Med Genet A. 2024 Sep 27. e63892

Bi-Allelic Splicing Variant, c.153-2A > C in TOMM7 Is Associated With Leigh Syndrome.

Mayuri Yeole, Purvi Majethia, Shahyan Siddiqui, Katta Mohan Girisha, Anju Shukla, Periyasamy Radhakrishnan, Vivekananda Bhat.

  Translocase of the outer mitochondrial membrane (TOMM) complex plays an important role in the transport of proteins from the cytoplasm into the mitochondria. TOMM7, one of the subunits of the TOMM complex, modulates its assembly and stability. Bi-allelic disease-causing variants in TOMM7 (MIM* 607980) have been previously reported in two unrelated families with a diverse phenotype of short stature, lipodystrophy, progeria, developmental delay, hypotonia, and skeletal dysplasia. We report a 4-month-old female child significantly affected with neonatal-onset hypotonia, lactic acidosis, optic atrophy, and neuroimaging findings suggestive of Leigh disease with a novel canonical splice variant, c.153-2A > C in TOMM7 (NM_019059.5). Further work done on cDNA of parents revealed the presence of shorter transcripts secondary to aberrant splicing.

Keywords:  Garg‐Mishra progeroid syndrome; TOMM complex; elevated lactate; mitochondria

DOI:  https://doi.org/10.1002/ajmg.a.63892