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A Comprehensive Approach to the Diagnosis of Leigh Syndrome Spectrum

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

Diagnostics 2024, 14(19), 2133; https://doi.org/10.3390/diagnostics14192133 - 25 Sep 2024

Cited by 1 | Viewed by 2423

Abstract

Background: Leigh syndrome spectrum (LSS) is a novel nomenclature that encompasses both classical Leigh syndrome and Leigh-like phenotypes. Given the heterogeneity of disease presentation, a new consensus published recently addressed the main issues and proposed general guidelines towards diagnosis. Based on these recommendations, we developed a simple pipeline that can be useful in the diagnosis of LSS. Methods: We combined previously published criteria with our own experience to achieve a diagnostic framework that can provide faster satisfactory results with fewer resources. Results: We suggest adding basic biochemical tests for amino acids, acylcarnitine, and urinary organic acids as parallel investigations, as these results can be obtained in a short time. This approach characterized 80% of our cohort and promoted specific intervention in 10% of confirmed cases. Conclusions: Genetic studies are crucial in the diagnosis of LSS, but they are time-consuming and might delay tailored interventions. Therefore, we suggest adding more affordable and less complex biochemical studies as primary tests when investigating treatable causes of LSS. Full article

(This article belongs to the Section Pathology and Molecular Diagnostics)

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14 pages, 537 KiB

Open AccessArticle

Leigh Syndrome Spectrum: A Portuguese Population Cohort in an Evolutionary Genetic Era

by Manuela Schubert Baldo, Célia Nogueira, Cristina Pereira, Patrícia Janeiro, Sara Ferreira, Charles M. Lourenço, Anabela Bandeira, Esmeralda Martins, Marina Magalhães, Esmeralda Rodrigues, Helena Santos, Ana Cristina Ferreira and Laura Vilarinho

Genes 2023, 14(8), 1536; https://doi.org/10.3390/genes14081536 - 27 Jul 2023

Cited by 5 | Viewed by 2783

Abstract

Mitochondrial diseases are the most common inherited inborn error of metabolism resulting in deficient ATP generation, due to failure in homeostasis and proper bioenergetics. The most frequent mitochondrial disease manifestation in children is Leigh syndrome (LS), encompassing clinical, neuroradiological, biochemical, and molecular features. It typically affects infants but occurs anytime in life. Considering recent updates, LS clinical presentation has been stretched, and is now named LS spectrum (LSS), including classical LS and Leigh-like presentations. Apart from clinical diagnosis challenges, the molecular characterization also progressed from Sanger techniques to NGS (next-generation sequencing), encompassing analysis of nuclear (nDNA) and mitochondrial DNA (mtDNA). This upgrade resumed steps and favored diagnosis. Hereby, our paper presents molecular and clinical data on a Portuguese cohort of 40 positive cases of LSS. A total of 28 patients presented mutation in mtDNA and 12 in nDNA, with novel mutations identified in a heterogeneous group of genes. The present results contribute to the better knowledge of the molecular basis of LS and expand the clinical spectrum associated with this syndrome. Full article

(This article belongs to the Section Genetic Diagnosis)

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18 pages, 2532 KiB

Open AccessArticle

Leigh Syndrome: Spectrum of Molecular Defects and Clinical Features in Russia

by Denis Kistol, Polina Tsygankova, Tatiana Krylova, Igor Bychkov, Yulia Itkis, Ekaterina Nikolaeva, Svetlana Mikhailova, Maria Sumina, Natalia Pechatnikova, Sergey Kurbatov, Fatima Bostanova, Ochir Migiaev and Ekaterina Zakharova

Int. J. Mol. Sci. 2023, 24(2), 1597; https://doi.org/10.3390/ijms24021597 - 13 Jan 2023

Cited by 13 | Viewed by 4805

Abstract

Leigh syndrome (LS), also known as infantile subacute necrotizing encephalopathy, is the most frequent mitochondrial disorder in children. Recently, more than 80 genes have been associated with LS, which greatly complicates the diagnosis. In this article, we present clinical and molecular findings of 219 patients with LS and give the detailed description of three cases with rare findings in nuclear genes MORC2, NARS2 and VPS13D, demonstrating wide genetic heterogeneity of this mitochondrial disease. The most common cause of LS in Russian patients are pathogenic variants in the SURF1 gene (44.3% of patients). The most frequent pathogenic variant is c.845_846delCT (66.0% of mutant alleles; 128/192), which is also widespread in Eastern Europe. Five main LS genes, SURF1, SCO2, MT-ATP6, MT-ND5 and PDHA1, account for 70% of all LS cases in the Russian Federation. Using next generation sequencing (NGS) technique, we were able to detect pathogenic variants in other nuclear genes: NDUFV1, NDUFS2, NDUFS8, NDUFAF5, NDUFAF6, NDUFA10, SUCLG1, GFM2, COX10, PMPCB, NARS2, PDHB and SLC19A3, including two genes previously associated with Leigh-like phenotypes—MORC2 and VPS13D. We found 49 previously undescribed nucleotide variants, including two deep intronic variants which affect splicing. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Genetics and Genomics in Russia)

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15 pages, 3418 KiB

Open AccessReview

Pathogenic Biallelic Mutations in ECHS1 in a Case with Short-Chain Enoyl-CoA Hydratase (SCEH) Deficiency-Case Report and Literature Review

by Carmen Muntean, Florin Tripon, Alina Bogliș and Claudia Bănescu

Int. J. Environ. Res. Public Health 2022, 19(4), 2088; https://doi.org/10.3390/ijerph19042088 - 13 Feb 2022

Cited by 10 | Viewed by 3803

Abstract

ECHS1 gene mutations are known to cause mitochondrial short-chain enoyl-CoA hydratase 1 deficiency, a neurodegenerative disorder characterized by psychomotor development delay, lactic acidosis, and basal ganglia lesions resembling Leigh syndrome. Short-chain enoyl-CoA hydratase 1 (ECHS1) deficiency is a very rare and new disorder, with a wide phenotypic spectrum and different outcomes ranging from neonatal death to survival into adulthood. Since the identification of ECHS1 deficiency in 2014, almost 63 patients with pathogenic mutations in the ECHS1 gene have been described to date. This paper focuses on the clinical and molecular findings as well as the evolution of a Caucasian girl diagnosed with ECHS1 deficiency who carries a new compound heterozygous mutation in the ECHS1 gene. Polymorphic symptoms, namely failure to thrive, significant global developmental delay/regression, movement disorders, ocular abnormalities, hearing loss, seizure, and cardiac myopathy, may be a challenge in mitochondrial disorder suspicion. Early diagnosis, an appropriate diet with valine restriction, and trigger avoidance are essential, as there is no effective therapy for the disease. This disorder influences life quality in these patients and their caregivers, and it has the potential to be fatal. Full article

(This article belongs to the Section Global Health)

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13 pages, 844 KiB

Open AccessReview

Accessory Subunits of the Matrix Arm of Mitochondrial Complex I with a Focus on Subunit NDUFS4 and Its Role in Complex I Function and Assembly

by Flora Kahlhöfer, Max Gansen and Volker Zickermann

Life 2021, 11(5), 455; https://doi.org/10.3390/life11050455 - 19 May 2021

Cited by 25 | Viewed by 4716

Abstract

NADH:ubiquinone-oxidoreductase (complex I) is the largest membrane protein complex of the respiratory chain. Complex I couples electron transfer to vectorial proton translocation across the inner mitochondrial membrane. The L shaped structure of complex I is divided into a membrane arm and a matrix arm. Fourteen central subunits are conserved throughout species, while some 30 accessory subunits are typically found in eukaryotes. Complex I dysfunction is associated with mutations in the nuclear and mitochondrial genome, resulting in a broad spectrum of neuromuscular and neurodegenerative diseases. Accessory subunit NDUFS4 in the matrix arm is a hot spot for mutations causing Leigh or Leigh-like syndrome. In this review, we focus on accessory subunits of the matrix arm and discuss recent reports on the function of accessory subunit NDUFS4 and its interplay with NDUFS6, NDUFA12, and assembly factor NDUFAF2 in complex I assembly. Full article

(This article belongs to the Special Issue Impaired Mitochondrial Bioenergetics under Pathological Conditions)

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