bims-curels 2024-10-20 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2024–10–20
eleven papers selected by
Cure Mito Foundation

Clinical and Genetic Spectrum of Patients With Mitochondrial Disease in a Pediatric Egyptian Cohort: Novel Variants and Phenotypic Expansion.
A case with short stature and proteinuria: atypical presentation of a family with m.3243A>G mutation.
Resolving Phenotypic Variability in Mitochondrial Diseases: Preliminary Findings of a Proteomic Approach.
A Comprehensive Approach to the Diagnosis of Leigh Syndrome Spectrum.
Consider the patient as a whole.
Phenotypic and molecular reanalysis of a cohort of patients with monogenic diabetes reveals a case of partial lipodystrophy due to the A8344G mutation in the mitochondrial DNA.
Hypoxia-mediated rescue of retinal ganglion cells deficient in mitochondrial complex I is independent of the hypoxia-inducible factor pathway.
Ndufs4 knockout mice with isolated complex I deficiency engage a futile adaptive brain response.
Meta-analysis of treatment outcomes for patients with m.11778G>A MT-ND4 Leber Hereditary Optic Neuropathy.
Mitochondrial transplantation: a promising strategy for treating degenerative joint diseases.
Critically unwell infants and children with mitochondrial disorders diagnosed by ultra-rapid genomic sequencing.

Am J Med Genet A. 2024 Oct 14. e63881

Clinical and Genetic Spectrum of Patients With Mitochondrial Disease in a Pediatric Egyptian Cohort: Novel Variants and Phenotypic Expansion.

Hebatallah M Hassaan, Angela Pyle, Nihal Almenabawy, Fiona M Robertson, Nour Elkhateeb, Marian Y Girgis, Iman Gamal El Din Mahmoud, Fawzia Amer, Mona Samaha, Yara Shaheen, Walaa ElNaggar, Doaa Abdoh, Dina Ahmed Mehaney, Iman Ehsan Abdel Meguid, Robert W Taylor, Robert McFarland, Laila Selim.

  Mitochondrial disorders exhibit clinical and genetic diversity. Nearly 400 distinct genes, located in both the mitochondrial and nuclear genomes, harbor pathogenic variants that can produce a broad spectrum of mitochondrial diseases. This work aims to explore the genetic etiology of a cohort of Egyptian pediatric patients who were clinically suspected of having a mitochondrial disorder. A total of 49 patients from 44 unrelated families were studied. Selection criteria included age below 18 years and meeting Morava criteria (a score ≥ 3). The mitochondrial disease criteria (MDC) have been developed to quantify the clinical picture and evaluate the probability of an underlying mitochondrial disorder Exome sequencing, including mitochondrial genome sequencing, was carried out for each participant. Causative variants likely responsible for the phenotypes were identified in 68% of the study population. The mitochondrial subgroup constituted 41% of the studied population with a median age of 4 years. No primary pathogenic variants in mitochondrial DNA were detected. Pathogenic or likely pathogenic variants in eight mitochondrial genes were identified in 78% of the mitochondrial cohort. Additionally, seven novel variants were identified. Nonmitochondrial diagnoses accounted for 27% of the study population. In 32% of cases, disease-causing variants were not identified. The current study underscores the diverse phenotypic and genetic landscape of mitochondrial disorders among Egyptian patients.

Keywords:  exome sequencing; gene; mitochondrial diseases; variants

DOI:  https://doi.org/10.1002/ajmg.a.63881
Turk J Pediatr. 2024 Oct 07. 66(4): 490-498

A case with short stature and proteinuria: atypical presentation of a family with m.3243A>G mutation.

Gönül Büyükyılmaz, Mihriban İnözü, Büşranur Çavdarlı.

   BACKGROUND: The mitochondrial DNA (mtDNA) m.3243A>G mutation is one of the most common pathogenic mtDNA variants. The phenotypes associated with this mutation range from asymptomatic induviduals to well-defined clinical syndromes, or non-syndromic mitochondrial disorders. Variable clinical features in pediatric cases may cause difficulty in diagnosis. Kidney involvement in this mutation is uncommon and reported on a case-by-case basis. Here, we report on a patient with m.3243A>G mutation, who presented with short stature and proteinuria, and his family, who share the same genotype but exhibit different heteroplasmy levels in different tissues and variable phenotypes.
CASE PRESENTATION: A 15-year-old male patient was admitted to the pediatric endocrinology department with short stature. His examinations revealed nephrotic range proteinuria, hearing loss, impaired glucose tolerance, and Wolf-Parkinson-White syndrome. From family history, it was learned that diabetes mellitus (DM) and progressive sensorineural hearing loss were common in this family. The patient's mother, who had chronic kidney disease, DM, and hearing loss, had died suddenly for an unknown reason. Considering the family history, a genetic analysis was performed for mitochondrial disease. Mitochondrial DNA analysis revealed a m.3243A>G mutation with 47% heteroplasmy in blood, 62% heteroplasmy in buccal cells, and 96% heteroplasmy in urothelial cells in our patient.
CONCLUSIONS: Short stature without any other complaint and renal involvement are rare findings in m.3243A>G mutation. In patients presenting with proteinuria, in the presence of conditions affecting many systems such as endocrine system pathologies, hearing loss, and cardiac pathologies, and in the presence of individuals with a similar family history of multiple organ involvement, mitochondrial diseases should be considered, and examined from this perspective. Our case illustrates the value of a detailed medical and family history.

Keywords:  m.3243A>G; maternally inherited diabetes and deafness; mitochondrial disease; proteinuria; short stature

DOI:  https://doi.org/10.24953/turkjpediatr.2024.4702
Int J Mol Sci. 2024 Oct 05. pii: 10731. [Epub ahead of print]25(19):

Resolving Phenotypic Variability in Mitochondrial Diseases: Preliminary Findings of a Proteomic Approach.

Michela Cicchinelli, Guido Primiano, Serenella Servidei, Michelangelo Ardito, Anna Percio, Andrea Urbani, Federica Iavarone.

  The introduction of new sequencing approaches into clinical practice has radically changed the diagnostic approach to mitochondrial diseases, significantly improving the molecular definition rate in this group of neurogenetic disorders. At the same time, there have been no equal successes in the area of in-depth understanding of disease mechanisms and few innovative therapeutic approaches have been proposed recently. In this regard, the identification of the molecular basis of phenotypic variability in primary mitochondrial disorders represents a key aspect for deciphering disease mechanisms with important therapeutic implications. In this study, we present data from proteomic investigations in two subjects affected by mitochondrial disease characterized by a different clinical severity and associated with the same variant in the TWNK gene, encoding the mitochondrial DNA and RNA helicase with a specific role in the mtDNA replisome. Heterozygous pathogenic variants in this gene are associated with progressive external ophthalmoplegia and ptosis, usually with adult onset. The overall results suggest an imbalance in glucose metabolism and ROS production/regulation, with possible consequences on the phenotypic manifestations of the enrolled subjects. Although the data will need to be validated in a large cohort, proteomic investigations have proven to be a valid approach for a deep understanding of these neurometabolic disorders.

Keywords:  PEO; mitochondria; mitochondrial diseases; omics technologies; proteomics

DOI:  https://doi.org/10.3390/ijms251910731
Diagnostics (Basel). 2024 Sep 25. pii: 2133. [Epub ahead of print]14(19):

A Comprehensive Approach to the Diagnosis of Leigh Syndrome Spectrum.

Manuela Schubert Baldo, Luísa Azevedo, Margarida Paiva Coelho, Esmeralda Martins, Laura Vilarinho.

   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.

Keywords:  Leigh syndrome spectrum; diagnosis; mitochondrial disorder; neurodegeneration

DOI:  https://doi.org/10.3390/diagnostics14192133
BMJ. 2024 Oct 18. 387 q2246

Consider the patient as a whole.

Zoë Halford.

DOI: https://doi.org/10.1136/bmj.q2246
Arch Endocrinol Metab. 2024 ;68 e230084

Phenotypic and molecular reanalysis of a cohort of patients with monogenic diabetes reveals a case of partial lipodystrophy due to the A8344G mutation in the mitochondrial DNA.

Pedro Campos Franco, Michelle Patrocinio, Aline Dantas Costa-Riquetto, Augusto Cezar Santomauro, Larissa Garcia Gomes, Milena G Teles.

Familial partial lipodystrophy (FPLD) is a very rare genetic disease characterized by insulin resistance due to a loss of subcutaneous fat from the extremities together with a progressive storage of fat around the face and neck and inside the abdomen. In over 50% of cases, molecular genetic testing reveals pathogenic variants in two nuclear genes, LMNA and PPARG. The case reported here refers to a woman phenotypically diagnosed with FPLD, who presented with diabetes and multiple cervical lipomatosis and in whom no variant had been found in the nuclear genes classically associated with this syndrome that could explain her phenotype. Genetic sequencing using a target panel containing 48 nuclear genes related to monogenic diabetes plus the whole mitochondrial genome revealed the mitochondrial variant m.A8344G in 84.1% heteroplasmy. Following molecular diagnosis, her phenotype was expanded with the recognition of additional clinical characteristics: mild sensorineural hearing loss, proximal myopathy, fatigue, cognitive impairment, sensory ataxia, cardiac abnormalities and, finally, muscle biopsy findings compatible with mitochondrial disease. Therefore, careful and detailed phenotypic and genotypic reanalysis proved crucial in improving molecular diagnosis in FPLD.

DOI: https://doi.org/10.20945/2359-4292-2023-0084
Sci Rep. 2024 10 15. 14(1): 24114

Hypoxia-mediated rescue of retinal ganglion cells deficient in mitochondrial complex I is independent of the hypoxia-inducible factor pathway.

Alexander M Warwick, Howard M Bomze, Luyu Wang, Ying Hao, Sandra S Stinnett, Sidney M Gospe.

  Continuous exposure to environmental hypoxia (11% O2) has been shown to markedly slow the progressive degeneration of retinal ganglion cells (RGCs) in a mouse model of mitochondrial optic neuropathy with RGC-specific deletion of the key mitochondrial complex I accessory subunit ndufs4. As a first step toward identifying the therapeutic mechanism of hypoxia in this model, we conducted a series of experiments to investigate the role of the hypoxia-inducible factor (HIF) regulatory pathway in RGC neuroprotection. Vglut2-Cre; ndufs4loxP/loxP mice were crossed with strains bearing floxed alleles of the negative HIF regulatory vhl or of the two major HIF α-subunit isoforms, Hif1α and Hif2α. Deletion of vhl within ndufs4-deficient RGCs failed to prevent RGC degeneration under normoxia, indicating that HIF activation is not sufficient to achieve RGC rescue. Furthermore, the rescue of ndufs4-deficient RGCs by hypoxia remained robust despite genetic inactivation of Hif1α and Hif2α. Our findings demonstrate that the HIF pathway is entirely dispensable to the rescue of RGCs by hypoxia. Future efforts to uncover key HIF-independent molecular pathways induced by hypoxia in this mouse model may be of therapeutic relevance to mitochondrial optic neuropathies such as Leber hereditary optic neuropathy.

Keywords:  Complex I; Hypoxia; Hypoxia-inducible factor; Leber hereditary optic neuropathy; Mitochondria; Retinal ganglion cell

DOI:  https://doi.org/10.1038/s41598-024-75916-x
Biochim Biophys Acta Proteins Proteom. 2024 Oct 10. pii: S1570-9639(24)00062-1. [Epub ahead of print] 141055

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

Melissa A E van de Wal, Cenna Doornbos, Janne Bibbe, Judith R Homberg, Clara van Karnebeek, Martijn A Huynen, Jaap Keijer, Evert M van Schothorst, Peter A C 't Hoen, Mirian C H Janssen, Merel J W Adjobo-Hermans, Mariusz R Wieckowski, Werner J H Koopman.

  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. SIGNIFICANCE: The 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.

Keywords:  Brain; Fatty acids; Leigh syndrome; Pathomechanism; Proteomics

DOI:  https://doi.org/10.1016/j.bbapap.2024.141055
Surv Ophthalmol. 2024 Oct 15. pii: S0039-6257(24)00130-9. [Epub ahead of print]

Meta-analysis of treatment outcomes for patients with m.11778G>A MT-ND4 Leber Hereditary Optic Neuropathy.

Nancy J Newman, Valérie Biousse, Patrick Yu-Wai-Man, Valerio Carelli, Catherine Vignal-Clermont, François Montestruc, Magali Taiel, José-Alain Sahel.

  Our aim was to assess the visual outcomes of patients with Leber hereditary optic neuropathy (LHON) harboring the m.11778G>A MT-ND4 mutation who had no treatment (natural history) or received idebenone or lenadogene nolparvovec. Efficacy outcomes included clinically relevant recovery (CRR) from nadir and final best-corrected visual acuity (BCVA). For the natural history and idebenone groups, we performed a systematic review of the literature and available clinical/regulatory reports. For the lenadogene nolparvovec group, all data from phase 3 studies were included. The overall effect and its 95% confidence interval (CI) were estimated using a random effects model. For each meta-analysis, patients had a mean age of approximately 30 years at vision loss and were mostly (≥78%) men. The CRR from nadir [95% CI] at eye level was 17% [7%; 30%] (n=316 eyes), 31% [24%; 40%] (n=313) and 59% [54%; 64%] (n=348) in untreated, idebenone-treated and lenadogene nolparvovec-treated patients, respectively. This gradient of efficacy was also observed with CRR at the patient level and final BCVA. There was a gradient of efficacy in all assessed visual outcomes, more marked for CRR than for final BCVA, with lenadogene nolparvovec gene therapy superior to idebenone treatment, and both superior to the natural history of the disease.

Keywords:  LHON; clinically relevant recovery; gene therapy; idebenone; lenadogene nolparvovec; meta-analysis; mitochondrial disease; natural history; visual acuity

DOI:  https://doi.org/10.1016/j.survophthal.2024.10.002
J Transl Med. 2024 Oct 15. 22(1): 941

Mitochondrial transplantation: a promising strategy for treating degenerative joint diseases.

Hong Luo, Yue Lai, Weili Tang, Guoyou Wang, Jianlin Shen, Huan Liu.

  The prevalence of age-related degenerative joint diseases, particularly intervertebral disc degeneration and osteoarthritis, is increasing, thereby posing significant challenges for the elderly population. Mitochondrial dysfunction is a critical factor in the etiology and progression of these disorders. Therapeutic interventions that incorporate mitochondrial transplantation exhibit considerable promise by increasing mitochondrial numbers and improving their functionality. Existing evidence suggests that exogenous mitochondrial therapy improves clinical outcomes for patients with degenerative joint diseases. This review elucidates the mitochondrial abnormalities associated with degenerative joint diseases and examines the mechanisms of mitochondrial intercellular transfer and artificial mitochondrial transplantation. Furthermore, therapeutic strategies for mitochondrial transplantation in degenerative joint diseases are synthesized, and the concept of engineered mitochondrial transplantation is proposed.

Keywords:  Degenerative joint diseases; Engineered mitochondria; Intervertebral disc degeneration; Mitochondrial transplantation; Osteoarthritis

DOI:  https://doi.org/10.1186/s12967-024-05752-0
Genet Med. 2024 Oct 14. pii: S1098-3600(24)00227-2. [Epub ahead of print] 101293

Critically unwell infants and children with mitochondrial disorders diagnosed by ultra-rapid genomic sequencing.

Megan Ball, Sophie E Bouffler, Christopher B Barnett, Mary-Louise Freckmann, Matthew F Hunter, Benjamin Kamien, Karin S Kassahn, Sebastian Lunke, Chirag V Patel, Jason Pinner, Tony Roscioli, Sarah A Sandaradura, Hamish S Scott, Tiong Y Tan, Mathew Wallis, Alison G Compton, David R Thorburn, Zornitza Stark, John Christodoulou.

   PURPOSE: To characterize the diagnostic and clinical outcomes of a cohort of critically ill infants and children with suspected mitochondrial disorders (MD) undergoing ultra-rapid genomic testing as part of a national program.
METHODS: Ultra-rapid genomic sequencing was performed in 454 families (genome sequencing: n=290, exome sequencing +/- mitochondrial DNA sequencing: n=164). In 91 individuals, MD was considered, prompting analysis using an MD virtual gene panel. These individuals were reviewed retrospectively and scored according to modified Nijmegen Mitochondrial Disease Criteria.
RESULTS: A diagnosis was achieved in 47% (43/91) of individuals, 40% (17/43) of whom had an MD. Seven additional individuals in whom an MD was not suspected were diagnosed with an MD following broader analysis. Gene-agnostic analysis led to the discovery of two novel disease genes, with pathogenicity validated through targeted functional studies (CRLS1 and MRPL39). Functional studies enabled diagnosis in another four individuals. Of the 24 individuals ultimately diagnosed with an MD, 79% had a change in management, which included 53% whose care was redirected to palliation.
CONCLUSION: Ultra-rapid genetic diagnosis of MD in acutely unwell infants and children is critical for guiding decisions about the need for additional investigations and clinical management.

Keywords:  Mitochondrial disorders; Neonatal; Paediatric; Rapid Genomics

DOI:  https://doi.org/10.1016/j.gim.2024.101293