Mitochondrial Syndrome Research Articles

A novel missense mutation in ISCA2 causes aberrant splicing and leads to multiple mitochondrial dysfunctions syndrome 4

BackgroundIron–sulfur cluster assembly 2 (ISCA2) deficiency is linked to an autosomal recessive disorder known as multiple mitochondrial dysfunctions syndrome 4 (MMDS4). This disorder is characterized by leukodystrophy and neuroregression. Currently, most of the reported patients are from Saudi Arabia. All these patients carry a homozygous founder variant (NM_194279.2:c.229G>A:p.Gly77Ser) in ISCA2.MethodsWe describe a patient who underwent full clinical evaluation, including metabolic, neurological, and radiological examinations. Standard genetic testing, including whole exome sequencing coupled with autozygome analysis, was undertaken, as were assessments of mitochondrial DNA (mtDNA) copy number and mtDNA sequencing on DNA extracted from blood and cultured fibroblasts. Functional workup consisted of splicing assessment of ISCA2 using RT-PCR, biochemical assessment of complex I status using dipstick assays, and mitochondrial respiration measurements using a Seahorse XFp analyzer.ResultsWe present the clinical and functional characterization of a novel homozygous ISCA2 missense variant (NM_194279.3:c.70A>G:p.Arg24Gly), leading to aberrant splicing in a patient presenting with neuroregression, generalized spasticity with exaggerated deep tendon reflexes and head lag, and progressive loss of acquired milestones. The novel variant was fully segregated in a wider family and was absent in a large control cohort, ethnically matching in-house exomes, local databases such as CGMdb and Saudi Human Genome Program, and ClinVar.ConclusionsOur analyses revealed that the variant is pathogenic, disrupting normal ISCA2 splicing and presumably leading to a truncated protein that disturbs metabolic pathways in patient-derived cells.

Long-term hematopoietic dysfunction in patients with large-scale mitochondrial DNA deletion syndromes.

Pearson syndrome (PS) and Kearns-Sayre syndrome (KSS) are single large-scale mitochondrial DNA deletion (SLSMD) syndromes. PS is characterized by severe, transient childhood cytopenia, whereas KSS typically manifests later in life without hematologic abnormalities. Despite distinct clinical presentations, both share a common mitochondrial DNA deletion. Recent observations suggest a potential link between PS progression and myeloid malignancy development, indicating that bone marrow failure (BMF) may be a key aspect of PS pathology and potentially universal across SLSMDs. This study explores longitudinal hematological manifestations of SLSMD syndromes, focusing on bone marrow (BM) dysfunction. Sixteen patients with SLSMDs (13 PS and 3 KSS) were followed, of whom 75% experienced cytopenia, necessitating blood transfusions in 56%. Despite achieving transfusion independence at a median age of 24 months, persistent hematological abnormalities were noted. Comprehensive longitudinal BM studies were conducted in 62% of subjects and consistently revealed signs of marrow dysfunction, even without concurrent cytopenia. Median BM cellularity at a median age of four years and eight months was 50%, with histological signs of dyserythropoiesis, abnormal megakaryocytes, and signs suggesting myelodysplasia. Reduced CD34+ counts and BM colony-forming unit capacity were noted, alongside chromosome 7 aberrations in 16% of patients on cytogenetic studies. Our findings establish BM dysfunction as a persistent hallmark of SLSMD syndromes, posing a risk of clonal evolution and acquisition of chromosome 7 aberrations. This aligns with recent literature, emphasizing enduring BMF in SLSMD syndromes and advocating for tailored hematological monitoring guidelines for this unique patient cohort.

Defects in the Maturation of Mitochondrial Iron-Sulfur Proteins: Biophysical Investigation of the MMDS3 Causing Gly104Cys Variant of IBA57.

Multiple mitochondrial dysfunctions syndrome type 3 (MMDS3) is a rare autosomal recessive mitochondrial leukoencephalopathy caused by biallelic pathogenic variants in the IBA57 gene. The gene protein product, IBA57, has an unknown role in iron-sulfur (Fe-S) cluster biogenesis but is required for the maturation of mitochondrial [4Fe-4S] proteins. To better understand the role of IBA57 in MMDS3, we have investigated the impact of the pathogenic p.Gly104Cys (c.310G > T) variant on the structural and functional properties of IBA57. The Gly104Cys variant has been associated with a severe MMDS3 phenotype in both compound heterozygous and homozygous states, and defects in the activity of mitochondrial respiratory complexes and lipoic acid-dependent enzymes have been demonstrated in the affected patients. Size exclusion chromatography, also coupled to multiple angle light scattering, NMR, circular dichroism, and fluorescence spectroscopy characterization has shown that the Gly104Cys variant does not impair the conversion of the homo-dimeric [2Fe-2S]-ISCA22 complex into the hetero-dimeric IBA57-[2Fe-2S]-ISCA2 but significantly affects the stability of IBA57, in both its isolated form and in complex with ISCA2, thus providing a rationale for the severe MMDS3 phenotype associated with this variant.

Phenotypic spectrum of iron-sulfur cluster assembly gene IBA57 mutations: c.286 T > C identified as a hotspot mutation in Chinese patients with a stable natural history.

Mutations in IBA57 disrupt iron-sulfur clusters maturation, causing a rare mitochondrial disease. Clinical manifestations vary from neonatal lethality to childhood-onset spastic paraparesis, yet the ethnic heterogeneity and natural history remain unclear, necessitating further exploration. This study aimed to delineate the genotype-phenotype correlation of IBA57 mutations by analyzing diverse clinical presentations. We report 11 Chinese patients and include literature-reported cases, totaling 61 patients enrolled for analysis. Clinical, neuroimaging, genetic, and disease progression information were collected. Among these, 46 presented as multiple mitochondrial dysfunctions syndrome 3 (MMDS3), with 58.7% originating from Chinese population. Based on disease course, we propose three clinical subtypes: neonatal, infant and childhood subtypes. Neonatal cases universally displayed hypotonia and respiratory distress at presentation, deceased within three months. Most infancy and childhood cases exhibited developmental regression and impaired motor function. Cavitating leukoencephalopathy was a typical neuroimaging finding in MMDS3 patients. The c.286 T > C mutation was reported in 85.2% of Chinese patients. A significantly lower mortality rate was observed compared to the non-Chinese group (P = 0.002), with a survival rate exceeding 90% at 5 years, indicating a relatively stable disease progression. Fifteen cases from three families manifested the spastic paraplegia 74 phenotype, demonstrating normal development before onset, with common clinical manifestations including spastic paraplegia (14/15), visual impairment (10/13), and peripheral neuropathy (9/13). In conclusion, this study indicates a hotspot mutation in Chinese and analyses the disease progression with different clinical subtypes.

Long Term Follow Up of a Family with A3243G Mitochondrial Syndrome.

To describe the clinical and multimodal imaging (MMI) features of a family (proband, sister and mother) with A3243G mitochondrial retinopathy and long-term follow up. Medical and imaging records were retrospectively evaluated. Multimodal imaging included ultra-widefield color fundus photography, fundus autofluorescence, and spectral-domain optical coherence tomography. Long-term MMI follow up ranged from 6 to 15 years and was available for each member. The proband (Case 1) exhibited rapidly progressive bilateral macular atrophy, corneal endothelial polymegathism, and an A3243G mutation in the mitochondrial DNA. The proband also endorsed a history of early-onset myocardial infarction (MI) ten years prior at the age of 42. The proband's sister (Case 2) only exhibited unilateral focal macular atrophy but admitted to a history of severe multiorgan systemic disease, including multiple sclerosis and major depression disorder. The proband's mother (Case 3), the only one with diabetes mellitus and hearing loss, originally presented with branch retinal vein occlusion in the right eye and pattern dystrophy in the left eye which evolved to geographic atrophy, OD > OS, 15 years later. A3243G mitochondrial syndrome can exhibit heterogenous ocular and systemic features, even within members of the same family. The development of the characteristic maculopathy with early-onset MI warrants genetic testing. Early cardiac and systemic screening may be recommended in individuals with characteristic retinal findings and genetic confirmation.

Mitochondrial Biomarkers and Metabolic Syndrome in Bipolar Disorder

The object of this study is test whether mitochondrial blood-based biomarkers are associated with markers of metabolic syndrome in bipolar disorder, hypothesizing higher lactate but unchanged cell-free circulating mitochondrial DNA levels in bipolar disorder patients with metabolic syndrome. In a cohort study, primary testing from the FondaMental Advanced Centers of Expertise for bipolar disorder (FACE-BD) was conducted, including 837 stable bipolar disorder patients. The I-GIVE validation cohort consists of 237 participants: stable and acute bipolar patients, non-psychiatric controls, and acute schizophrenia patients. Multivariable regression analyses show significant lactate association with triglycerides, fasting glucose and systolic and diastolic blood pressure. Significantly higher levels of lactate were associated with presence of metabolic syndrome after adjusting for potential confounding factors. Mitochondrial-targeted metabolomics identified distinct metabolite profiles in patients with lactate presence and metabolic syndrome, differing from those without lactate changes but with metabolic syndrome. Circulating cell-free mitochondrial DNA was not associated with metabolic syndrome. This thorough analysis mitochondrial biomarkers indicate the associations with lactate and metabolic syndrome, while showing the mitochondrial metabolites can further stratify metabolic profiles in patients with BD. This study is relevant to improve the identification and stratification of bipolar patients with metabolic syndrome and provide potential personalized-therapeutic opportunities.

Ancestral allele of DNA polymerase gamma modifies antiviral tolerance

Mitochondria are critical modulators of antiviral tolerance through the release of mitochondrial RNA and DNA (mtDNA and mtRNA) fragments into the cytoplasm after infection, activating virus sensors and type-I interferon (IFN-I) response1–4. The relevance of these mechanisms for mitochondrial diseases remains understudied. Here we investigated mitochondrial recessive ataxia syndrome (MIRAS), which is caused by a common European founder mutation in DNA polymerase gamma (POLG1)5. Patients homozygous for the MIRAS variant p.W748S show exceptionally variable ages of onset and symptoms5, indicating that unknown modifying factors contribute to disease manifestation. We report that the mtDNA replicase POLG1 has a role in antiviral defence mechanisms to double-stranded DNA and positive-strand RNA virus infections (HSV-1, TBEV and SARS-CoV-2), and its p.W748S variant dampens innate immune responses. Our patient and knock-in mouse data show that p.W748S compromises mtDNA replisome stability, causing mtDNA depletion, aggravated by virus infection. Low mtDNA and mtRNA release into the cytoplasm and a slow IFN response in MIRAS offer viruses an early replicative advantage, leading to an augmented pro-inflammatory response, a subacute loss of GABAergic neurons and liver inflammation and necrosis. A population databank of around 300,000 Finnish individuals6 demonstrates enrichment of immunodeficient traits in carriers of the POLG1 p.W748S mutation. Our evidence suggests that POLG1 defects compromise antiviral tolerance, triggering epilepsy and liver disease. The finding has important implications for the mitochondrial disease spectrum, including epilepsy, ataxia and parkinsonism.

Twists in genetic mitochondria: Unraveling a case of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes overlapping with myoclonic epilepsy with ragged red fibers

This case report presents a 23-year-old female with a complex medical history, initially diagnosed with juvenile myoclonic epilepsy, later discovered to have the m.3243A>G variant associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Despite a typical myoclonic epilepsy with ragged red fibers (MERRF) phenotype, genetic testing confirmed a singular MELAS mutation. The patient exhibited diverse symptoms, including seizures, chronic migraines, myoclonus, and visual disturbances. Diagnostic studies revealed basal ganglia calcifications and progressive brain MRI abnormalities consistent with mitochondrial dysfunction. Additionally, ophthalmologic exams identified features indicative of MELAS pigmentary retinopathy. The discussion highlights the clinical and genetic diversity of mitochondrial disorders, emphasizing the challenges in distinguishing overlapping phenotypes. The patient’s mitochondrial DNA heteroplasmy influenced the variable onset and severity of symptoms. The case underscores the importance of comprehensive genetic investigations, as the m.3243A>G variant is associated with both MELAS and MERRF, leading to diagnostic complexities. Management strategies, primarily symptom-focused due to the lack of a standardized treatment approach, include prophylactic arginine, taurine, and coenzyme Q10 supplementation. The patient’s response to various medications, including vagal nerve stimulator placement, Botox injections, and novel treatments like ASP0367, demonstrates the ongoing efforts to address symptoms and improve quality of life. This report contributes to the understanding of mitochondrial overlap syndromes, offering insights into the diagnostic challenges and management complexities associated with MELAS and MERRF. The case underscores the need for a multidisciplinary approach, combining clinical, genetic, and therapeutic considerations, to optimize care for individuals with mitochondrial encephalopathies.

Climate Stressors and Physiological Dysregulations: Mechanistic Connections to Pathologies.

This review delves into the complex relationship between environmental factors, their mechanistic cellular and molecular effects, and their significant impact on human health. Climate change is fueled by industrialization and the emission of greenhouse gases and leads to a range of effects, such as the redistribution of disease vectors, higher risks of disease transmission, and shifts in disease patterns. Rising temperatures pose risks to both food supplies and respiratory health. The hypothesis addressed is that environmental stressors including a spectrum of chemical and pathogen exposures as well as physical and psychological influences collectively impact genetics, metabolism, and cellular functions affecting physical and mental health. The objective is to report the mechanistic associations linking environment and health. As environmental stressors intensify, a surge in health conditions, spanning from allergies to neurodegenerative diseases, becomes evident; however, linkage to genetic-altered proteomics is more hidden. Investigations positing that environmental stressors cause mitochondrial dysfunction, metabolic syndrome, and oxidative stress, which affect missense variants and neuro- and immuno-disorders, are reported. These disruptions to homeostasis with dyslipidemia and misfolded and aggregated proteins increase susceptibility to cancers, infections, and autoimmune diseases. Proposed interventions, such as vitamin B supplements and antioxidants, target oxidative stress and may aid mitochondrial respiration and immune balance. The mechanistic interconnections of environmental stressors and disruptions in health need to be unraveled to develop strategies to protect public health.

Unmasking the mitochondrial mystery: febrile illness exposing a rare cause of refractory epilepsy with unique imaging features: a case report

BackgroundMitochondrial DNA polymerase, which is encoded by the POLG (polymerase gamma) gene, is responsible for the replication of the mitochondrial genome. Around 300 pathogenic variants have been identified in this gene and the clinical impact of POLG mutations is highly variable in both severity and phenotype. Our case had a clinical presentation distinct from the known mitochondrial syndromes associated with POLG gene, in the form of refractory focal seizures against a background of progressive ataxia, late symptom onset and rapid progression. In addition, our patient had signal changes in the pons with a unique radiological feature not previously described in this disease.Case presentationWe describe a 46-year-old lady with adult onset refractory focal seizures against a background of progressive cognitive impairment and ataxia preceded by a febrile illness. MRI brain showed T2/FLAIR hyperintensities involving right frontal and parietal cortex, bilateral thalamus, pons and cerebellum. Clinical exome and mitochondrial genome sequencing identified homozygous missense variation in exon 13 of the POLG gene. Among these above radiological features, a novel radiological finding in a case of POLG mutation was the transverse pontine signal change, which has not been described till date to our knowledge. She was being treated and given increasing doses and combinations of anti-seizure medications, but succumbed to the illness after two months.ConclusionsThis case highlights a unique radiological finding in the form of transverse T2/FLAIR signal change in pons, in a case of genetically proven case of POLG mutation along with other common radiological features. The triad of clinical features, which were characterised by progressive ataxia, cognitive impairment and refractory focal seizures occurring in combination, were unusual in a middle aged lady with POLG mutation.

Long-Term Hematopoietic Dysfunction in Patients with Single Large-Scale Mitochondrial DNA Deletion Syndromes

Pearson syndrome (PS) is the only single large-scale mitochondrial DNA deletion syndrome (SLSMDs) presenting substantial hematologic manifestations, usually a severe though transient cytopenia of childhood. Recently, progression to myeloid malignancies has been described among PS patients. Older PS patients, as well as patients with SLSMDs presenting with Kearns-Sayre syndrome (KSS) or with progressive external ophthalmoplegia (PEO), do not display hematologic abnormalities. Since the underlying mitochondrial DNA deletion is similar in all SLSMDs, we hypothesized that bone marrow (BM) dysfunction is a common and persistent manifestation in these patients. We studied 16 patients with molecular-confirmed SLSMDs: 13 with PS, and three with KSS. The median age at diagnosis was 25 months (range 2-136 months). Seventy-five percent of patients presented with cytopenia in infancy, and 56% required blood products. Resolution of cytopenia occurred in 92% of this subgroup, at a median age of 24 months (range 12-39 months). BM studies were performed in all patients, and 56% of patients had multiple BM evaluations. All BM biopsies examined showed signs of marrow dysfunction, including in patients without a history of cytopenia. Median BM cellularity was 50% (range 30-80%) at a median age of 5 years. BM samples showed a paucity of precursor myeloid cells, signs of dyserythropoiesis, and abnormal or missing megakaryocytes. We report low hematopoietic stem and progenitor cell functionality in patients with SLSMDs: The median CD34+ count was 0.68% (range 0.27-1.92%, expected range 1-2%). BM colony forming unit (CFU) capacity was reduced in SLSMD patients: the median CFU in patients was 280 per 10 6 cells compared to 1090 per 10 6 cells in healthy controls (p=0.004). Conventional cytogenetic analysis was done on 10 patients (62%), and FISH analysis was done on 15 patients (93%). Monosomy 7 was identified in seven patients (44%): in one patient the monosomy 7 resolved in a follow-up BM assay. Another patient with signs of myelodysplasia and 30% of the BM cells having monosomy 7 was referred to an allogeneic bone marrow transplantation. To conclude, long-term BM dysfunction is evident in all patients with SLSMD and includes a risk of developing clonal evolution and monosomy 7. This data, combined with other recent publications, highlights the ongoing marrow failure and suggest that SLSMD syndromes should be included under inherited BM failure syndromes.

Ataxia Syndrome With Hearing Loss and Nephronophthisis Associated With a Novel Homozygous Variant in XPNPEP3.

Biallelic variants in XPNPEP3 are associated with a rare mitochondrial syndrome characterized by nephronophthisis leading to kidney failure, essential tremor, hearing loss, seizures, and intellectual disability. Only 2 publications on this condition are available. We report a man with a complex ataxia syndrome, hearing loss, and kidney failure associated with a new biallelic variant in XPNPEP3. Clinical evaluation, neuroimaging studies, a kidney biopsy, and whole genome sequencing (WGS) were applied. Since the phenotype was compatible with a mitochondrial disease, a muscle biopsy with morphological and mitochondrial biochemical investigations was performed. Axial ataxia, cerebellar atrophy, hearing loss, myopathy, ptosis, supranuclear palsy, and kidney failure because of nephronophthisis were the prominent features in this case. WGS revealed the novel biallelic variant c.766C>T (p.Gln256*) in XPNPEP3. A muscle biopsy revealed COX negative fibers, a few ragged red fibers, and ultrastructural mitochondrial changes. Enzyme activity in respiratory chain complex IV was reduced in muscle and fibroblasts. This is the first report of a slowly progressive cerebellar ataxia associated with a novel biallelic variant in XPNPEP3. Abnormalities typical for mitochondrial disease and the slow progression of kidney disease are also striking. Our report expands the spectrum of XPNPEP3-related diseases.

BOLA3 and NFU1 link mitoribosome iron-sulfur cluster assembly to multiple mitochondrial dysfunctions syndrome.

The human mitochondrial ribosome contains three [2Fe-2S] clusters whose assembly pathway, role, and implications for mitochondrial and metabolic diseases are unknown. Here, structure-function correlation studies show that the clusters play a structural role during mitoribosome assembly. To uncover the assembly pathway, we have examined the effect of silencing the expression of Fe-S cluster biosynthetic and delivery factors on mitoribosome stability. We find that the mitoribosome receives its [2Fe-2S] clusters from the GLRX5-BOLA3 node. Additionally, the assembly of the small subunit depends on the mitoribosome biogenesis factor METTL17, recently reported containing a [4Fe-4S] cluster, which we propose is inserted via the ISCA1-NFU1 node. Consistently, fibroblasts from subjects suffering from 'multiple mitochondrial dysfunction' syndrome due to mutations in BOLA3 or NFU1 display previously unrecognized attenuation of mitochondrial protein synthesis that contributes to their cellular and pathophysiological phenotypes. Finally, we report that, in addition to their structural role, one of the mitoribosomal [2Fe-2S] clusters and the [4Fe-4S] cluster in mitoribosome assembly factor METTL17 sense changes in the redox environment, thus providing a way to regulate organellar protein synthesis accordingly.

Wide diagnostic and genotypic spectrum in patients with suspected mitochondrial disease

BackgroundMitochondrial Diseases (MDs) are a diverse group of neurometabolic disorders characterized by impaired mitochondrial oxidative phosphorylation and caused by pathogenic variants in more than 400 genes. The implementation of next-generation sequencing (NGS) technologies helps to increase the understanding of molecular basis and diagnostic yield of these conditions. The purpose of the study was to investigate diagnostic and genotypic spectrum in patients with suspected MD. The comprehensive analysis of mtDNA variants using Sanger sequencing was performed in the group of 83 unrelated individuals with clinically suspected mitochondrial disease. Additionally, targeted next generation sequencing or whole exome sequencing (WES) was performed for 30 patients of the study group.ResultsThe overall diagnostic rate was 21.7% for the patients with suspected MD, increasing to 36.7% in the group of patients where NGS methods were applied. Mitochondrial disease was confirmed in 11 patients (13.3%), including few classical mitochondrial syndromes (MELAS, MERRF, Leigh and Kearns-Sayre syndrome) caused by pathogenic mtDNA variants (8.4%) and MDs caused by pathogenic variants in five nDNA genes. Other neuromuscular diseases caused by pathogenic variants in seven nDNA genes, were confirmed in seven patients (23.3%).ConclusionThe wide spectrum of identified rare mitochondrial or neurodevelopmental diseases proves that MD suspected patients would mostly benefit from an extensive genetic profiling allowing rapid diagnostics and improving the care of these patients.

P355 Mitochondrial depletion syndrome TK2 deficiency can be treated with oral deoxynucleosides

P355 Mitochondrial depletion syndrome TK2 deficiency can be treated with oral deoxynucleosides

Deoxyguanosine kinase deficiency and recurrent spontaneous pneumothorax: a case report

BackgroundDeoxyguanosine kinase deficiency is mainly manifested by hepatic and neurological damage, hence it belongs to the hepatocerebral form of mitochondrial deoxyribonucleic acid depletion syndrome. The association between deoxyguanosine kinase deficiency and recurrent spontaneous pneumothorax has not currently been reported.Case presentationA 12-year-old Russian boy with deoxyguanosine kinase deficiency, a recipient of a liver transplant with amyotrophy secondary to his mitochondriopathy, presented with recurrent spontaneous bilateral pneumothorax refractory to drainage and surgery.ConclusionTo our knowledge, this is the first documented case of deoxyguanosine kinase deficiency associated with recurrent spontaneous pneumothorax, which could be considered a late complication of deoxyguanosine kinase deficiency. At this point, this is only an association and further studies and research need to be performed to help confirm the pathogenesis of this association.

Volatile anaesthetic toxicity in the genetic mitochondrial disease Leigh syndrome

BackgroundVolatile anaesthetics are widely used in human medicine. Although generally safe, hypersensitivity and toxicity can occur in rare cases, such as in certain genetic disorders. Anaesthesia hypersensitivity is well-documented in a subset of mitochondrial diseases, but whether volatile anaesthetics are toxic in this setting has not been explored. MethodsWe exposed Ndufs4(−/−) mice, a model of Leigh syndrome, to isoflurane (0.2–0.6%), oxygen 100%, or air. Cardiorespiratory function, weight, blood metabolites, and survival were assessed. We exposed post-symptom onset and pre-symptom onset animals and animals treated with the macrophage depleting drug PLX3397/pexidartinib to define the role of overt neuroinflammation in volatile anaesthetic toxicities. ResultsIsoflurane induced hyperlactataemia, weight loss, and mortality in a concentration- and duration-dependent manner from 0.2% to 0.6% compared with carrier gas (O2 100%) or mock (air) exposures (lifespan after 30-min exposures ∗P<0.05 for isoflurane 0.4% vs air or vs O2, ∗∗P<0.005 for isoflurane 0.6% vs air or O2; 60-min exposures ∗∗P<0.005 for isoflurane 0.2% vs air, ∗P<0.05 for isoflurane 0.2% vs O2). Isoflurane toxicity was significantly reduced in Ndufs4(−/−) exposed before CNS disease onset, and the macrophage depleting drug pexidartinib attenuated sequelae of isoflurane toxicity (survival ∗∗∗P=0.0008 isoflurane 0.4% vs pexidartinib plus isoflurane 0.4%). Finally, the laboratory animal standard of care of 100% O2 as a carrier gas contributed significantly to weight loss and reduced survival, but not to metabolic changes, and increased acute mortality. ConclusionsIsoflurane is toxic in the Ndufs4(−/−) model of Leigh syndrome. Toxic effects are dependent on the status of underlying neurologic disease, largely prevented by the CSF1R inhibitor pexidartinib, and influenced by oxygen concentration in the carrier gas.

Clinical, radiological, biochemical and molecular characterization of a new case with multiple mitochondrial dysfunction syndrome due to IBA57: Lysine and tryptophan metabolites as potential biomarkers

Iron‑sulfur clusters (FeS) are one of the most primitive and ubiquitous cofactors used by various enzymes in multiple pathways. Biosynthesis of FeS is a complex multi-step process that is tightly regulated and requires multiple machineries. IBA57, along with ISCA1 and ISCA2, play a role in maturation of [4Fe-4S] clusters which are required for multiple mitochondrial enzymes including mitochondrial Complex I, Complex II, lipoic acid synthase, and aconitase. Pathogenic variants in IBA57 have been associated with multiple mitochondrial dysfunctions syndrome 3 (MMDS3) characterized by infantile to early childhood-onset psychomotor regression, optic atrophy and nonspecific dysmorphism. Here we report a female proband who had prenatal involvement including IUGR and microcephaly and developed subacute psychomotor regression at the age of 5 weeks in the setting of preceding viral infection. Brain imaging revealed cortical malformation with polymicrogyria and abnormal signal alteration in brainstem and spinal cord. Biochemical analysis revealed increased plasma glycine and hyperexcretion of multiple organic acids in urine, raising the concern for lipoic acid biosynthesis defects and mitochondrial FeS assembly defects. Molecular analysis subsequently detected compound heterozygous variants in IBA57, confirming the diagnosis of MMDS3. Although the number of MMDS3 patients are limited, certain degree of genotype-phenotype correlation has been observed. Unusual brain imaging in the proband highlights the need to include mitochondrial disorders as differential diagnoses of structural brain abnormalities. Lastly, in addition to previously known biomarkers including high blood lactate and plasma glycine levels, the increase of 2-hydroxyadipic and 2-ketoadipic acids in urine organic acid analysis, in the appropriate clinical context, should prompt an evaluation for the lipoic acid biosynthesis defects and mitochondrial FeS assembly defects.

Deep brain stimulation in a pediatric dystonia patient with cochlear implants and mitochondrial disorder: novel application of a frameless stereotactic system and navigating the anesthesia choice and neurosurgical complexities. Illustrative case.

This report presents a case of medically refractory dystonia in a pediatric patient successfully treated with bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) while under general anesthesia by using microelectrode recordings (MERs) with intraoperative computed tomography (CT). The patient was an 18-year-old female with primary dystonia secondary to mitochondrial Leigh syndrome. Her past medical history was significant for complex partial epilepsy and hearing loss treated with cochlear implants. Her cochlear implants precluded anatomical targeting via magnetic resonance imaging. Additionally, the patient could not tolerate awake surgery with MER. The decision was made to proceed with bilateral STN DBS with intraoperative CT with the patient under general anesthesia. The patient's cochlear implants made standard frame placement difficult, so navigation was performed with the Nexframe system. Recordings were obtained with the patient under general anesthesia with ketamine, dexmedetomidine, and remifentanil. At the 3- and 6-month follow-ups, the patient demonstrated marked improvement in dystonia without neurological complications. This is the first case of dystonia secondary to Leigh syndrome treated with DBS. Additionally, the authors describe the novel use of the Nexframe for DBS lead placement in a pediatric patient. This demonstrates that STN DBS with the use of MER and intraoperative CT can be a safe and effective method of treating dystonia in certain pediatric patients.

Understanding the impact of pediatric single large-scale mtDNA deletion syndromes on caregivers: Burdens and challenges.

Single large-scale mitochondrial deletion syndromes (SLSMDS) are ultra-rare, progressive multi-system diseases that make children largely dependent on their caregivers for both medical and non-medical needs. Yet, few studies have examined the burden felt among caregivers. As part of a larger research study, 42 caregivers of children with SLSMDS completed two surveys to assess caregiver burden. The Mitochondrial Care Network Patient Needs Survey (MCN-PNS) is a novel assessment that examines the logistical, time, and financial costs experienced by caregivers of children with SLSMDS. The Zarit Burden Interview (ZBI-22) is a validated assessment that examines caregivers' psychological health. Results demonstrate the unique burden experienced by caregivers of children with SLSMDS. One notable finding was the high psychological burden. Nearly 90% of caregivers experience psychological burden, with 20% of caregivers at risk for anxiety and depression. Caregivers were primarily concerned about what the future held for their child. Additional burdens included the time required to coordinate the child's healthcare visits and financial strains. Caregivers reported minimal delays in establishing care with a mitochondrial care specialist and felt confident in their understanding of their child's disease and treatment(s). Overall, there is a need for expanded logistical, financial, and psychological support from mitochondrial disease centers and advocacy groups for caregivers of children with SLSMDS.