A novel de novo heterozygous pathogenic variant in the SDHA gene results in childhood onset bilateral optic atrophy and cognitive impairment

Zehavi, Yoav; Saada, Ann; Jabaly-Habib, Haneen; Dessau, Moshe; Shaag, Avraham; Elpeleg, Orly; Spiegel, Ronen

doi:10.1007/s11011-021-00671-1

Cited by 4 publications

(2 citation statements)

References 18 publications

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“…SDH deficiency, also known as mitochondrial complex II deficiency, is a rare cause of mitochondrial respiratory chain defects with a prevalence of 2-23%. It is essential for both oxidation process of succinate to fumarate in the citric acid cycle and reduction of ubiquinone in electron transfer chain contributing to the formation of ATP [Rasheed et al, 2018;Zehavi et al, 2021].…”

Section: Discussionmentioning

confidence: 99%

Two Patients Diagnosed as Succinate Dehydrogenase Deficiency: Case Report

et al. 2023

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Introductıon: Succinate dehydrogenase deficiency, also known as mitochondrial complex II deficiency, is a rare inborn error of metabolism, accounting for approximately 2% of mitochondrial disease. Mutations in the four genes SDHA, B, C,and D have been reported resulting in diverse clinical presentations. The vast majority of clinically affected individuals reported in the literature harbor genetic variants within the SDHA gene and present with a Leigh syndrome phenotype, clinically defined as a subacute necrotizing encephalopathy. Case Report: Herein, we report the first case of a 7-year-old child who was diagnosed as having succinate dehydrogenase deficiency. The affected child presented at 1 year of age with encephalopathy and developmental regression following viral illnesses. MRI changes supported a clinical diagnosis of Leigh syndrome and c.1328C>Q and c.872A>C SDHA variants were identified as compound heterozygous. Mitochondrial cocktail treatment including L-carnitine, riboflavin, thiamine, biotin, and ubiquinone was started. Mild clinical improvement was observed after treatment. He is now unable to walk and speak. The second patient, a 21-year-old woman, presented with generalized muscle weakness, easy fatigability, and cardiomyopathy. Investigations revealed increased lactate level of 67.4 mg/dL (4.5–19.8) with repeatedly increased plasma alanine levels 1,272 µmol/L (200–579). We administered carnitine, coenzyme, riboflavin, and thiamine for empirical therapy with the suspicion of mitochondrial disease. Clinical exome sequencing revealed compound heterozygous variants NM_004168.4:c.1945_1946del (p.Leu649GlufsTer4) at exon 15 of the SDHA gene and NM_004168.4:c.1909-12_1909-11del at intron 14 of SDHA gene. Discussion and Conclusion: There are several very different presentations including Leigh syndrome, epileptic encephalopathy, and cardiomyopathy. Some cases present following viral illness; this feature is not specific to mitochondrial complex II deficiency and occurs in many other mitochondrial disease presentations. There is no cure for complex II deficiency, though some reported patients showed clinical improvement following riboflavin therapy. Riboflavin is not the only therapeutic intervention that is available to patients with an isolated complex II deficiency and various other compounds have shown promise in the treatment of symptoms, including L-carnitine and ubiquinone. Treatment alternatives such as parabenzoquinone EPI-743 and rapamycin are under study in the treatment of the disease.

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Section: Discussionmentioning

confidence: 99%

Two Patients Diagnosed as Succinate Dehydrogenase Deficiency: Case Report

et al. 2023

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“…In 2015, the first Chinese patient with mitochondrial complex II deficiency was reported by Ma et al and two frame-shift variants (c.117delG and c.220insT) in SDHA were identified (Ma et al, 2014). To date, over twenty different pathogenic variants in SDHA have been reported to cause mitochondrial diseases, and the majority of the affected patients presented with Leigh syndrome (Baskovich et al, 2016;Birch-Machin et al, 2000;Horvath et al, 2006;Levitas et al, 2010;Ma et al, 2014;Parfait et al, 2000;Renkema et al, 2015;Taylor et al, 1996;Van Coster et al, 2003;Zehavi et al, 2021). Most of the variants are missense and follow the autosomal recessive inheritance.…”

Section: Discussionmentioning

confidence: 99%

Whole‐exome sequencing identified novel variants in three Chinese Leigh syndrome pedigrees

Yang

Cao

Song

et al. 2022

American J of Med Genetics Pt A

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Leigh syndrome (LS), the most common mitochondrial disease in early childhood, usually manifests variable neurodegenerative symptoms and typical brain magnetic resonance imaging (MRI) lesions. To date, pathogenic variants in more than 80 genes have been identified. However, there are still many cases without molecular diagnoses, and thus more disease-causing variants need to be unveiled. Here, we presented three clinically suspected LS patients manifesting neurological symptoms including developmental delay, hypotonia, and epilepsy during the first year of age, along with symmetric brain lesions on MRI. We explored disease-associated variants in patients and their nonconsanguineous parents by whole-exome sequencing and subsequent Sanger sequencing verification. Sequencing data revealed three pairs of diseaseassociated compound heterozygous variants: c.1A>G (p.Met1?) and 409G>C (p. Asp137His) in SDHA, c.1253G>A (p.Arg418His) and 1300C>T (p.Leu434Phe) in NARS2, and c.5C>T (p.Ala2Val) and 773T>G (p.Leu258Trp) in ECHS1. Among them, the likely pathogenic variants c.409G>C (p.Asp137His) in SDHA, c.1300C>T (p. Leu434Phe) in NARS2, and c.773T>G (p.Leu258Trp) in ECHS1 were newly identified. Segregation analysis indicated the possible disease-causing nature of the novel variants. In silico prediction and three-dimensional protein modeling further suggested the potential pathogenicity of these variants. Our discovery of novel variants expands the gene variant spectrum of LS and provides novel evidence for genetic counseling.

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Molecular Mechanisms behind Inherited Neurodegeneration of the Optic Nerve

Maresca

Carelli

2021

Biomolecules

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Inherited neurodegeneration of the optic nerve is a paradigm in neurology, as many forms of isolated or syndromic optic atrophy are encountered in clinical practice. The retinal ganglion cells originate the axons that form the optic nerve. They are particularly vulnerable to mitochondrial dysfunction, as they present a peculiar cellular architecture, with axons that are not myelinated for a long intra-retinal segment, thus, very energy dependent. The genetic landscape of causative mutations and genes greatly enlarged in the last decade, pointing to common pathways. These mostly imply mitochondrial dysfunction, which leads to a similar outcome in terms of neurodegeneration. We here critically review these pathways, which include (1) complex I-related oxidative phosphorylation (OXPHOS) dysfunction, (2) mitochondrial dynamics, and (3) endoplasmic reticulum-mitochondrial inter-organellar crosstalk. These major pathogenic mechanisms are in turn interconnected and represent the target for therapeutic strategies. Thus, their deep understanding is the basis to set and test new effective therapies, an urgent unmet need for these patients. New tools are now available to capture all interlinked mechanistic intricacies for the pathogenesis of optic nerve neurodegeneration, casting hope for innovative therapies to be rapidly transferred into the clinic and effectively cure inherited optic neuropathies.

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A novel de novo heterozygous pathogenic variant in the SDHA gene results in childhood onset bilateral optic atrophy and cognitive impairment

Cited by 4 publications

References 18 publications

Two Patients Diagnosed as Succinate Dehydrogenase Deficiency: Case Report

Two Patients Diagnosed as Succinate Dehydrogenase Deficiency: Case Report

Whole‐exome sequencing identified novel variants in three Chinese Leigh syndrome pedigrees

Molecular Mechanisms behind Inherited Neurodegeneration of the Optic Nerve

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