Leigh Syndrome Research Articles

Enhancing genomic disorder prediction through Feynman Concordance and Interpolated Nearest Centroid techniques.

Clinical biomedical applications of genomic technologies are extensive and provide possibilities to enhance healthcare covering the span of medical talents. Genome disorder prediction is an important issue in biomedical research. Genome disorders cause multivariate diseases such as cancer, dementia, diabetes, Leigh syndrome, etc. Existing machine and deep learning-based methods were introduced to forecast genome disorders. However, the genome prediction outcomes were not sufficient. To address this issue, propose a new method called Quadratic Feynman Polynomial Interpolated and Vector Nearest Centroid-based (QFPI-VNC) for acutely predicting the genome disorder with improved sensitivity and specificity. First, we utilized medical data about children from a public genomes dataset and applied it to Linear Quadratic and Feynman Kac Genome filtering to obtain computationally efficient filtered results. Next, the results are fed to the Concordance Correlated Polynomial Interpolation with the purpose of extracting genome wide data in an accurate manner. Finally, the features extracted are fused and fed to the Support Vector and Nearest Centroid model for genome disorder prediction. Experimental investigations of the proposed method employing the genome dataset confirm that the performance of the proposed method is prospective and in the scope of acceptance with relative to state-of-the-art methods in terms of convergence speed, recognition rate, sensitivity, and specificity. Results suggest that the QFPI-VNC method produces the best performance with a higher genome disease detection rate by 14%, accuracy by 11%, sensitivity by 14% specificity by 12%, and lesser convergence speed by 29% than compared to state-of-the-art methods.

Clinical characteristics of children with MT-TK gene m.8344A>G variation

Objective: To summarize the clinical characteristics of children carrying the m.8344A>G variant of MT-TK gene. Methods: A case series study was conducted to retrospectively collect data of 22 children with mitochondrial disease caused by MT-TK gene m.8344A>G variation who were treated at the Department of Neurology of Beijing Children's Hospital of Capital Medical University from January 2012 to January 2024. Their clinical data, laboratory tests, muscle pathology, genetic testing, and the follow-up results were analyzed. Pearson correlation analysis was used for correlation analysis. Results: Among the 22 children, there were 13 boys and 9 girls. The age of onset was 5.00 (2.75, 9.00) years. Fifteen children had myoclonic epilepsy with ragged-red fibers (MERRF), 3 had Leigh syndrome (LS), and 4 had LS-MERRF overlap syndrome (LS-MERRF). Myoclonus presented and worsened progressively in all 15 MERRF children, with 10 as the initial symptom and 5 developing progressively during the disease course. Myoclonus was predominantly focal, worsening with fine motor tasks or stress. Electroencephalogram monitoring in the 15 MERRF children revealed myoclonic seizures in 10 children, with 6 classified as myoclonic epilepsy, and 4 as subcortical myoclonus. Two children had generalized myoclonic seizures, and 1 each had absence seizures and generalized seizures. Twelve children had cerebellar ataxia, 10 children exhibited exercise intolerance, and 8 children had muscle weakness. Magnetic resonance imaging (MRI) revealed periventricular white matter involvement in 1 child and bilateral hippocampal involvement in 1 child, likely due to frequent seizures. All 3 children with LS exhibited developmental regressions, accompanied with 2 symptoms include cerebellar ataxia, muscle weakness, and dysphagia. The clinical manifestations of 4 LS-MERRF overlap children presented with combined features of MERRF and LS. Cranial MRI in the 7 LS and LS-MERRF children showed brainstem involvement (all affecting the midbrain) in 6 children and basal ganglia involvement in 4 children. Among the 22 children, 12 had m.8344A>G variant levels >90%, 3 had >80%-90%, 4 had >70%-80%, and 3 had >60%-70%. Higher variant level correlated with the LS phenotype and earlier onset age (r=0.47, -0.50; P=0.018 and 0.029, respectively). Sanger sequencing in 19 mothers revealed m.8344A>G variations in 18, with 4 showing exercise intolerance. Follow-up of 13 children on antimyoclonic treatment showed>75% reduction in seizures with levetiracetam monotherapy in 2 children, with combination therapy required in others. Most achieved >50% seizures reduction within 2 years, but the effectiveness declined with disease progression. Conclusions: The m.8344A>G variant is rare, with MERRF being the most common phenotype, while LS and LS-MERRF are less common. Children with higher ratio of the m.8344A>G variant are more likely to present LS phenotype. Myoclonus, primarily focal, is a key feature, with levetiracetam as the first-line treatment and benzodiazepines recommended for refractory cases.

Disease models of Leigh syndrome: From yeast to organoids.

Leigh syndrome (LS) is a severe mitochondrial disease that results from mutations in the nuclear or mitochondrial DNA that impairs cellular respiration and ATP production. Mutations in more than 100 genes have been demonstrated to cause LS. The disease most commonly affects brain development and function, resulting in cognitive and motor impairment. The underlying pathogenesis is challenging to ascertain due to the diverse range of symptoms exhibited by affected individuals and the variability in prognosis. To understand the disease mechanisms of different LS-causing mutations and to find a suitable treatment, several different model systems have been developed over the last 30 years. This review summarizes the established disease models of LS and their key findings. Smaller organisms such as yeast have been used to study the biochemical properties of causative mutations. Drosophila melanogaster, Danio rerio, and Caenorhabditis elegans have been used to dissect the pathophysiology of the neurological and motor symptoms of LS. Mammalian models, including the widely used Ndufs4 knockout mouse model of complex I deficiency, have been used to study the developmental, cognitive, and motor functions associated with the disease. Finally, cellular models of LS range from immortalized cell lines and trans-mitochondrial cybrids to more recent model systems such as patient-derived induced pluripotent stem cells (iPSCs). In particular, iPSCs now allow studying the effects of LS mutations in specialized human cells, including neurons, cardiomyocytes, and even three-dimensional organoids. These latter models open the possibility of developing high-throughput drug screens and personalized treatments based on defined disease characteristics captured in the context of a defined cell type. By analyzing all these different model systems, this review aims to provide an overview of past and present means to elucidate the complex pathology of LS. We conclude that each approach is valid for answering specific research questions regarding LS, and that their complementary use could be instrumental in finding treatment solutions for this severe and currently untreatable disease.

Ndufs4 knockout mice with isolated complex I deficiency engage a futile adaptive brain response

Paediatric Leigh syndrome (LS) is an early-onset and fatal neurodegenerative disorder lacking treatment options. LS is frequently caused by mutations in the NDUFS4 gene, encoding an accessory subunit of mitochondrial complex I (CI), the first complex of the oxidative phosphorylation (OXPHOS) system. Whole-body Ndufs4 knockout (KO) mice (WB-KO mice) are widely used to study isolated CI deficiency, LS pathology and interventions. These animals develop a brain-specific phenotype via an incompletely understood pathomechanism. Here we performed a quantitative analysis of the sub-brain proteome in six-weeks old WB-KO mice vs. wildtype mice. Brain regions comprised of a brain slice (BrSl), cerebellum (CB), cerebral cortex (CC), hippocampus (HC), inferior colliculus (IC), and superior colliculus (SC). Proteome analysis demonstrated similarities between CC/HC, and between IC/SC, whereas BrSl and CB differed from these two groups and each other. All brain regions displayed greatly reduced levels of two CI structural subunits (NDUFS4, NDUFA12) and an increased level of the CI assembly factor NDUFAF2. The level of CI-Q module subunits was significantly more reduced in IC/SC than in BrSl/CB/CC/HC, whereas other OXPHOS complex levels were not reduced. Gene ontology and pathway analysis demonstrated specific and common proteome changes between brain regions.Across brain regions, upregulation of cold-shock-associated proteins, mitochondrial fatty acid (FA) oxidation and synthesis (mtFAS) were the most prominent. FA-related pathways were predominantly upregulated in CB and HC. Based upon these results, we argue that stimulation of these pathways is futile and pro-pathological and discuss alternative strategies for therapeutic intervention in LS. SignificanceThe Ndufs4 knockout mouse model is currently the most relevant and most widely used animal model to study the brain-linked pathophysiology of human Leigh Syndrome (LS) and intervention strategies. We demonstrate that the Ndufs4 knockout brain engages futile and pro-pathological responses. These responses explain both negative and positive outcomes of intervention studies in Leigh Syndrome mice and patients, thereby guiding novel intervention opportunities.

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

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.

Characterization of Shy1, the Schizosaccharomyces pombe homolog of human SURF1

Cytochrome c oxidase (complex IV) is the terminal enzyme in the mitochondrial respiratory chain. As a rare neurometabolic disorder caused by mutations in the human complex IV assembly factor SURF1, Leigh Syndrome (LS) is associated with complex IV deficiency. In this study, we comprehensively characterized Schizosaccharomyces pombe Shy1, the homolog of human SURF1. Bioinformatics analysis revealed that Shy1 contains a conserved SURF1 domain that links to the biogenesis of complex IV and shares high structural similarity with its homologs in Saccharomyces cerevisiae and humans. Our study showed that Shy1 is required for the expression of mtDNA-encoded genes and physically interacts with structural subunits and assembly factors of complex IV. Interestingly, Rip1, the subunit of ubiquinone-cytochrome c oxidoreductase or cytochrome bc1 complex (complex III), can also co-immunoprecipitate with Shy1, suggesting Shy1 may be involved in the assembly of the mitochondrial respiratory chain supercomplexes. This conclusion is further corroborated by our BN-PAGE analysis. Unlike its homologs, deletion of shy1 does not critically disrupt respiratory chain assembly, indicating the presence of the compensatory mechanism(s) within S. pombe that ensure mitochondrial functionality. Collectively, our investigation elucidates that Shy1 plays a pivotal role in the sustainability of the regular function of mitochondria by participating in the assembly of complex IV in S. pombe.

New Insights into Mitochondria in Health and Diseases.

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.

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

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.

Cannabidiol ameliorates mitochondrial disease via PPARγ activation in preclinical models

Mutations in mitochondrial energy-producing genes lead to a heterogeneous group of untreatable disorders known as primary mitochondrial diseases (MD). Leigh syndrome (LS) is the most common pediatric MD and is characterized by progressive neuromuscular affectation and premature death. Here, we show that daily cannabidiol (CBD) administration significantly extends lifespan and ameliorates pathology in two LS mouse models, and improves cellular function in fibroblasts from LS patients. CBD delays motor decline and neurodegenerative signs, improves social deficits and breathing abnormalities, decreases thermally induced seizures, and improves neuropathology in affected brain regions. Mechanistically, we identify peroxisome proliferator-activated receptor gamma (PPARγ) as a key nuclear receptor mediating CBD’s beneficial effects, while also providing proof of dysregulated PPARγ expression and activity as a common feature in both mouse neurons and fibroblasts from LS patients. Taken together, our results provide the first evidence for CBD as a potential treatment for LS.

Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome.

Mitochondria transfer is a recently described phenomenon in which donor cells deliver mitochondria to acceptor cells1-3. One possible consequence of mitochondria transfer is energetic support of neighbouring cells; for example, exogenous healthy mitochondria can rescue cell-intrinsic defects in mitochondrial metabolism in cultured ρ0 cells or Ndufs4-/- peritoneal macrophages4-7. Exposing haematopoietic stem cells to purified mitochondria before autologous haematopoietic stem cell transplantation allowed for treatment of anaemia in patients with large-scale mitochondrial DNA mutations8,9, and mitochondria transplantation was shown to minimize ischaemic damage to the heart10-12, brain13-15 and limbs16. However, the therapeutic potential of using mitochondria transfer-based therapies to treat inherited mitochondrial diseases is unclear. Here we demonstrate improved morbidity and mortality of the Ndufs4-/- mouse model of Leigh syndrome (LS) in multiple treatment paradigms associated with mitochondria transfer. Transplantation of bone marrow from wild-type mice, which is associated with release of haematopoietic cell-derived extracellular mitochondria into circulation and transfer of mitochondria to host cells in multiple organs, ameliorates LS in mice. Furthermore, administering isolated mitochondria from wild-type mice extends lifespan, improves neurological function and increases energy expenditure of Ndufs4-/- mice, whereas mitochondria from Ndufs4-/- mice did not improve neurological function. Finally, we demonstrate that cross-species administration of human mitochondria to Ndufs4-/- mice also improves LS. These data suggest that mitochondria transfer-related approaches can be harnessed to treat mitochondrial diseases, such as LS.

Cellular protection and preservation of bioenergetics by the novel compound SBT-589 in a fibroblast model of Leigh syndrome

Cellular protection and preservation of bioenergetics by the novel compound SBT-589 in a fibroblast model of Leigh syndrome

Downregulation of two mitochondria-related miRNAs ameliorates the Leigh syndrome phenotype in Ndufs4 KO mice

Downregulation of two mitochondria-related miRNAs ameliorates the Leigh syndrome phenotype in Ndufs4 KO mice

IARS2 mutations lead to Leigh syndrome with a combined oxidative phosphorylation deficiency

BackgroundLeigh syndrome (LS) is a common mitochondrial disease caused by mutations in both mitochondrial and nuclear genes. Isoleucyl-tRNA synthetase 2 (IARS2) encodes mitochondrial isoleucine-tRNA synthetase, and variants in IARS2 have been reported to cause LS. However, the pathogenic mechanism of IARS2 variants is still unclear.MethodsTwo unrelated patients, a 4-year-old boy and a 5-year-old boy diagnosed with LS, were recruited, and detailed clinical data were collected. The DNA of the patients and their parents was isolated from the peripheral blood for the identification of pathogenic variants using next-generation sequencing and Sanger sequencing. The ClustalW program, allele frequency analysis databases (gnomAD and ExAc), and pathogenicity prediction databases (Clinvar, Mutation Taster and PolyPhen2) were used to predict the conservation and pathogenicity of the variants. The gene expression level, oxygen consumption rate (OCR), respiratory chain complex activity, cellular adenosine triphosphate (ATP) production, mitochondrial membrane potential (MMP) and mitochondrial reactive oxygen species (ROS) levels were measured in patient-derived lymphocytes and IARS2-knockdown HEK293T cells to evaluate the pathogenicity of the variants.ResultsWe reported 2 unrelated Chinese patients manifested with LS who carried biallelic IARS2 variants (c.1_390del and c.2450G > A from a 4-year-old boy, and c.2090G > A and c.2122G > A from a 5-year-old boy), of which c.1_390del and c.2090G > A were novel. Functional studies revealed that the patient-derived lymphocytes carrying c.1_390del and c.2450G > A variants exhibited impaired mitochondrial function due to severe mitochondrial complexes I and III deficiencies, which was also found in IARS2-knockdown HEK293T cells. The compensatory experiments in vitro cell models confirmed the pathogenicity of IARS2 variants since re-expression of wild-type IARS2 rather than mutant IARS2 could rescue complexes I and III deficiency, oxygen consumption, and cellular ATP content in IARS2 knockdown cells.ConclusionOur results not only expand the gene mutation spectrum of LS, but also reveal for the first time the pathogenic mechanism of IARS2 variants due to a combined deficiency of mitochondrial complexes I and III, which is helpful for the clinical diagnosis of IARS2 mutation-related diseases.

Dldhcri3 zebrafish exhibit altered mitochondrial ultrastructure, morphology, and dysfunction partially rescued by probucol or thiamine.

Dihydrolipoamide dehydrogenase (DLD) deficiency is a recessive mitochondrial disease caused by variants in DLD, the E3 subunit of mitochondrial α-keto (or 2-oxo) acid dehydrogenase complexes. DLD disease symptoms are multisystemic, variably manifesting as Leigh syndrome, neurodevelopmental disability, seizures, cardiomyopathy, liver disease, fatigue, and lactic acidemia. While most DLD disease symptoms are attributed to dysfunction of the pyruvate dehydrogenase complex, the effects of other α-keto acid dehydrogenase deficiencies remain unclear. Current therapies for DLD deficiency are ineffective, with no vertebrate animal model available for preclinical study. We created a viable Danio rerio (zebrafish) KO model of DLD deficiency, dldhcri3. Detailed phenotypic characterization revealed shortened larval survival, uninflated swim bladder, hepatomegaly and fatty liver, and reduced swim activity. These animals displayed increased pyruvate and lactate levels, with severe disruption of branched-chain amino acid catabolism manifest as increased valine, leucine, isoleucine, α-ketoisovalerate, and α-ketoglutarate levels. Evaluation of mitochondrial ultrastructure revealed gross enlargement, severe cristae disruption, and reduction in matrix electron density in liver, intestines, and muscle. Therapeutic modeling of candidate therapies demonstrated that probucol or thiamine improved larval swim activity. Overall, this vertebrate model demonstrated characteristic phenotypic and metabolic alterations of DLD disease, offering a robust platform to screen and characterize candidate therapies.

Severe mitochondrial encephalomyopathy caused by de novo variants in OPA1 gene.

Mitochondria adjust their shape in response to the different energetic and metabolic requirements of the cell, through extremely dynamic fusion and fission events. Several highly conserved dynamin-like GTPases are involved in these processes and, among those, the OPA1 protein is a key player in the fusion of inner mitochondrial membranes. Hundreds of monoallelic or biallelic pathogenic gene variants have been described in OPA1, all associated with a plethora of clinical phenotypes without a straightforward genotype-phenotype correlation. Here we report two patients harboring novel de novo variants in OPA1. DNA of two patients was analyzed using NGS technology and the pathogenicity has been evaluated through biochemical and morphological studies in patient's derived fibroblasts and in yeast model. The two patients here reported manifest with neurological signs resembling Leigh syndrome, thus further expanding the clinical spectrum associated with variants in OPA1. In cultured skin fibroblasts we observed a reduced amount of mitochondrial DNA (mtDNA) and altered mitochondrial network characterized by more fragmented mitochondria. Modeling in yeast allowed to define the deleterious mechanism and the pathogenicity of the identified gene mutations. We have described two novel-single OPA1 mutations in two patients characterized by early-onset neurological signs, never documented, thus expanding the clinical spectrum of this complex syndrome. Moreover, both yeast model and patients derived fibroblasts showed mitochondrial defects, including decreased mtDNA maintenance, correlating with patients' clinical phenotypes.

Phenotypic assessment of Cox10 variants and their implications for Leigh Syndrome

ObjectivesCox10 is an enzyme required for the activity of cytochrome c oxidase. Humans who lack at least one functional copy of Cox10 have a form of Leigh Syndrome, a genetic disease that is usually fatal in infancy. As more human genomes are sequenced, new alleles are being discovered; whether or not these alleles encode functional proteins remains unclear. Thus, we set out to measure the phenotypes of many human Cox10 variants by expressing them in yeast cells.ResultsWe successfully expressed the reference sequence and 25 variants of human Cox10 in yeast. We quantitated the ability of these variants to support growth on nonfermentable media and directly measured cytochrome c oxidase activity. 11 of these Cox10 variants supported approximately half or more the cytochrome c oxidase activity compared to the reference sequence. All of the strains containing those 11 variants also grew robustly using a nonfermentable carbon source. Cells expressing the other variants showed low cytochrome c oxidase activity and failed to grow on nonfermentable media.

The clinical and genetic spectrum of mitochondrial diseases in China: A multicenter retrospective cross-sectional study.

Mitochondrial diseases (MtDs) present diverse clinical phenotypes, yet large-scale studies are hindered by their rarity. This retrospective, multicenter study, conducted across five Chinese hospitals' neurology departments from 2009 to 2019, aimed to address this gap. Nationwide, 1351 patients were enrolled, with a median onset age of 14.0 (18.5) years. The predominant phenotype was mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) (45.0%). Mitochondrial DNA (mtDNA) mutations were prevalent (87.4%), with m.3243A>G being the most common locus (48.7%). Meanwhile, POLG mutations in nuclear DNA (nDNA) accounted for 16.5%. Comparative analysis based on age groups (with a cut-off at 14 years) revealed the highest prevalence of MELAS, with Leigh syndrome (LS) and chronic progressive external ophthalmoplegia (CPEO) being the second most common phenotypes in junior and senior groups, respectively. Notably, the most commonly mutated nuclear genes varied across age groups. In conclusion, MELAS predominated in this Chinese MtD cohort, underscored by m.3243A>G and POLG as principal mtDNA mutations and pathogenic nuclear genes. The phenotypic and genotypic disparities observed among different age cohorts highlight the complex nature of MtDs.

Endocrine Disorders in Children with Primary Mitochondrial Diseases: Single-Center Experience.

Endocrine abnormalities may represent the only clinical manifestation of primary mitochondrial disorders. This study aimed to evaluate the endocrinological characteristics of mitochondrial disease in our cohort. A total of twenty-six pediatric patients diagnosed with mitochondrial disease were categorized on the basis of their specific genetic abnormalities. The auxologic data, pubertal development, and, based on their clinical symptoms, hormonal profiles were obtained. Twelve of the cohort of 26 patients (46%) were female. In 15 of the patients (57.6%), their mitochondrial disease (MD) was caused by nuclear DNA mutations (nDNA group). Four patients had Leigh syndrome, 2 patients had LHON syndrome, 2 patients had MELAS, and 1 patient had KSS clinical phenotype. The median age at diagnosis was 2.91 (0.59-16.8) years, and the median age at first endocrinologic evaluation was 4.62 (1.26-18) years. The mean height SDS was -1.34 ± 2.12, and the mean BMI SDS was -0.82 ± 1.96 for all patients. Of the 26 patients, 6 (23%) had a range of hormonal deficits. Ovarian insufficiency, central adrenal insufficiency, central hypothyroidism, diabetes mellitus, and critical illness-related adrenal insufficiency were all observed. Three of the patients were initially monitored in the endocrine clinic for hormone deficiencies but it was later determined that the hormonal abnormalities were caused by underlying mitochondrial disease. Individuals diagnosed with mitochondrial disease, particularly those with specific genetic abnormalities, are considered a high-risk group for developing hormonal deficits. Endocrine diseases could be one of the primary mitochondrial disorders' early warning symptoms.

Demographic characteristics, diagnostic challenges, treatment patterns, and caregiver burden of mitochondrial diseases: a retrospective cross-sectional study

BackgroundThis study aimed to explore the demographic characteristics, diagnostic challenges, treatment patterns, and caregiver burden of mitochondrial diseases.MethodsThis retrospective cross-sectional study enrolled patients diagnosed with mitochondrial diseases from the Department of Neurology at Peking University First Hospital between January 2010 and December 2021. A questionnaire covering demographic characteristics, diagnostic dilemma, treatment, economic aspects, and caregiver stress was administered, and disability was assessed using the modified Rankin Scale (mRS).ResultsA total of 183 patients (mean age: 16 (IQR: 12–25), 49.72% males) were enrolled, including 124 pediatric patients and 59 adult patients. MELAS (106. 57.92%) and Leigh syndrome (37, 20.22%) were predominant among the mitochondrial disease subtypes. Among them, 132 (72.13%) patients were initially misdiagnosed with other diseases, 58 (31.69%) patients visited 2 hospitals before confirmed as mitochondrial disease, and 39 (21.31%) patients visited 3 hospitals before confirmed as mitochondrial disease. Metabolic modifiers were the most common type of drugs used, including several dietary supplements such as L-carnitine (117, 63.93%), Coenzyme Q10 (102, 55.74%), idebenone (82, 44.81%), and vitamins (99, 54.10%) for proper mitochondrial function. Mothers are the primary caregivers for both children (36.29%) and adults (38.98%). The mRS score ranged from 0 to 5, 92.35% of the patients had different degrees of disability due to mitochondrial disease. The average monthly treatment cost was 3000 RMB for children and 3100 RMB for adults.ConclusionsThis study provided valuable insights into the characteristics and challenges of mitochondrial diseases, which underscores the need for improved awareness, diagnostic efficiency, and comprehensive support for patients and caregivers.

Cranial and spinal nerve enhancement in SURF1-associated Leigh syndrome

A 23-month-old boy with poor growth, developmental delay, and hypotonia presented with acute onset of ataxia and fatigue. Magnetic resonance imaging (MRI) of the brain and spinal cord was performed as part of diagnostic work-up. MRI showed bilateral symmetrical lesions in basal ganglia, midbrain, and brainstem consistent with Leigh syndrome. Signal abnormalities were also present within the cervical cord, with enhancement of multiple cranial, spinal, and cauda equina nerve roots. Genetic testing confirmed compound heterozygosity for two pathogenic variants in SURF1 implicated in Leigh syndrome. Whilst nerve root enhancement has been described in other mitochondrial disorders, we believe this is the first published case of both cranial and spinal nerve root enhancement in Leigh syndrome.Graphical