Optic neuropathy linked to ACAD9 pathogenic variants: A potentially riboflavin-responsive disorder?

Guéguen, Naïg; Piarroux, Julie; Sarzi, Emmanuelle; Benkirane, Mehdi; Manes, Gae͏̈l; Delettre, Cécile; Amedro, Pascal; Leboucq, Nicolas; Kœnig, M.; Meyer, Pierre; Meunier, Isabelle; Reynier, Pascal; Lenaers, Guy; Roubertie, Agathe

doi:10.1016/j.mito.2021.05.002

Cited by 5 publications

(8 citation statements)

References 14 publications

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“…OXPHOS enzyme and citrate synthase activities in muscle tissue (Patient 5) or fibroblasts (Patients 8 and 10) were assessed spectrophotometrically using standard procedures. 26,27,32 Thirty-seven and 100 internal control samples were used in the experiments with muscle and fibroblasts, respectively. The mitochondrial fraction of muscle crude homogenates 26 or fibroblast cultures 27,32 was subjected to activity measurements.…”

Section: Enzyme Activity Assaysmentioning

confidence: 99%

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Variants in Mitochondrial ATP Synthase Cause Variable Neurologic Phenotypes

Zech

Kopajtich

Steinbrücker

et al. 2022

Annals of Neurology

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Objective ATP synthase (ATPase) is responsible for the majority of ATP production. Nevertheless, disease phenotypes associated with mutations in ATPase subunits are extremely rare. We aimed at expanding the spectrum of ATPase‐related diseases. Methods Whole‐exome sequencing in cohorts with 2,962 patients diagnosed with mitochondrial disease and/or dystonia and international collaboration were used to identify deleterious variants in ATPase‐encoding genes. Findings were complemented by transcriptional and proteomic profiling of patient fibroblasts. ATPase integrity and activity were assayed using cells and tissues from 5 patients. Results We present 10 total individuals with biallelic or de novo monoallelic variants in nuclear ATPase subunit genes. Three unrelated patients showed the same homozygous missense ATP5F1E mutation (including one published case). An intronic splice‐disrupting alteration in compound heterozygosity with a nonsense variant in ATP5PO was found in one patient. Three patients had de novo heterozygous missense variants in ATP5F1A, whereas another 3 were heterozygous for ATP5MC3 de novo missense changes. Bioinformatics methods and populational data supported the variants’ pathogenicity. Immunohistochemistry, proteomics, and/or immunoblotting revealed significantly reduced ATPase amounts in association to ATP5F1E and ATP5PO mutations. Diminished activity and/or defective assembly of ATPase was demonstrated by enzymatic assays and/or immunoblotting in patient samples bearing ATP5F1A‐p.Arg207His, ATP5MC3‐p.Gly79Val, and ATP5MC3‐p.Asn106Lys. The associated clinical profiles were heterogeneous, ranging from hypotonia with spontaneous resolution (1/10) to epilepsy with early death (1/10) or variable persistent abnormalities, including movement disorders, developmental delay, intellectual disability, hyperlactatemia, and other neurologic and systemic features. Although potentially reflecting an ascertainment bias, dystonia was common (7/10). Interpretation Our results establish evidence for a previously unrecognized role of ATPase nuclear‐gene defects in phenotypes characterized by neurodevelopmental and neurodegenerative features. ANN NEUROL 2022;91:225–237

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Section: Enzyme Activity Assaysmentioning

confidence: 99%

“…26,27,32 Thirty-seven and 100 internal control samples were used in the experiments with muscle and fibroblasts, respectively. The mitochondrial fraction of muscle crude homogenates 26 or fibroblast cultures 27,32 was subjected to activity measurements.…”

Section: Enzyme Activity Assaysmentioning

confidence: 99%

Variants in Mitochondrial ATP Synthase Cause Variable Neurologic Phenotypes

Zech

Kopajtich

Steinbrücker

et al. 2022

Annals of Neurology

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“…28 Importantly, riboflavin treatment (20 mg/kg/day) improves long-distance visual acuity. 30 Furthermore, patients with disease onset below 1 year of age, which are riboflavin-responsive have a statistically significantly better survival rate with oral riboflavin treatment, in contrast to untreated patients. 28 Patients usually present lactic acidosis but, unfortunately, there is no specific biochemical marker for this disorder.…”

Section: Clinical Presentationmentioning

confidence: 99%

“…33,34 This explains why the main clinical symptoms are those of a mitochondrial cytopathy, and therefore it is not clear if there is any role of the mFAO function for ACAD9 in the pathology. Interestingly, riboflavin supplementation has been shown to significantly rescue complex I activity in vitro in some patients 30 but unfortunately not in all. 28 Despite its difficult biochemical diagnosis, it is essential to diagnose ACAD9 deficiency using molecular genetic testing since this disorder represents a rare cause of complex I deficiency improved by treatment.…”

Section: Pathophysiologymentioning

confidence: 99%

“…This explains why the main clinical symptoms are those of a mitochondrial cytopathy, and therefore it is not clear if there is any role of the mFAO function for ACAD9 in the pathology. Interestingly, riboflavin supplementation has been shown to significantly rescue complex I activity in vitro in some patients 30 but unfortunately not in all 28 …”

Section: Understanding the Pathophysiology Of Unusual Clinical Signsmentioning

confidence: 99%

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Fifty years of research on mitochondrial fatty acid oxidation disorders: The remaining challenges

Vianey‐Saban,

Guffon,

Fouilhoux

et al. 2023

J of Inher Metab Disea

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Since the identification of the first disorder of mitochondrial fatty acid oxidation (FAOD) in 1973, more than twenty defects have been identified. Although there are some differences, most FAOD have similar clinical signs, which are mainly due to energy depletion and toxicity of accumulated metabolites. However, some of them have an unusual clinical phenotype or specific clinical signs. This manuscript focuses on what we have learnt so far on the pathophysiology of these disorders which present with clinical signs that are not typical of categorical FAOD. It also highlights that some disorders have not yet been identified and tries to make assumptions to explain why. It also deals with new treatments under consideration in FAOD, including triheptanoin and similar anaplerotic substrates, ketone body treatments, RNA and gene therapy approaches. Finally, it suggests challenges for the diagnosis of FAOD in the coming years, both for symptomatic patients and for those diagnosed through newborn screening. The ultimate goal would be to identify all the patients born with FAOD and ensure for them the best possible quality of life.Take home messageTentative hypotheses to improve the diagnosis and the treatment of fatty acid oxidation defects.This article is protected by copyright. All rights reserved.

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A retrospective study of the yield of next‐generation sequencing in the diagnosis of developmental and epileptic encephalopathies and epileptic encephalopathies in 0–12 years aged children at a single tertiary care hospital in South India

Murthy,

Banerjee,

Shetty

et al. 2024

Epileptic Disorders

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ObjectiveStudies on the genetic yield of developmental and epileptic encephalopathy and Epileptic encephalopathies using next‐generation sequencing techniques are sparse from the Indian subcontinent. Hence, the study was conducted to assess the yield of genetic testing and the proportion of children where a positive genetic yield influenced treatment decisions.MethodsIn this retrospective observational study, electronic medical records of children (0–12 years) with suspected genetic epilepsy who underwent genetic testing using whole exome sequencing, focused exome sequencing and epilepsy gene panels were retrieved. Genetic yield was ascertained based on the detection of pathogenic and likely pathogenic variants.ResultsA total of 100 patients with epilepsy underwent genetic testing. A yield of 53.8% (42/78) was obtained. Pathogenic variants were identified in 18 (42.8%) cases and likely pathogenic variants in 24 (57.1%) cases. Yield was 66.6% each through whole exome sequencing, focused exome sequencing and 40% through Epilepsy gene panels (p = .07). Yield was not statistically significant across different age groups (p = .2). It was however found to significantly vary across different epilepsy syndromes with maximum yield in Epilepsy in infancy with migrating focal seizures in 2 (100%), followed by developmental and epileptic encephalopathy unspecified in 14 (77.7%), Dravet syndrome in 14 (60.8%), early infantile developmental and epileptic encephalopathy in 3 (60%), infantile epileptic spasm syndrome in 5 (35.7%), and other epileptic encephalopathies in 4 (30.7%) cases (p = .04). After genetic diagnosis and drug optimization, drug‐refractory proportion reduced from 73.8% to 45.3%. About half of the cases achieved seizure control.SignificanceA reasonably high yield of 53.8% was obtained irrespective of the choice of panel or exome or age group using next‐generation sequencing‐based techniques. Yield was however higher in certain epilepsy syndromes and low in Infantile epileptic spasms syndrome. A specific genetic diagnosis facilitated tailored treatment leading to seizure freedom in 28.6% and marked seizure reduction in 54.7% cases.

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Optic neuropathy linked to ACAD9 pathogenic variants: A potentially riboflavin-responsive disorder?

Cited by 5 publications

References 14 publications

Variants in Mitochondrial ATP Synthase Cause Variable Neurologic Phenotypes

Variants in Mitochondrial ATP Synthase Cause Variable Neurologic Phenotypes

Fifty years of research on mitochondrial fatty acid oxidation disorders: The remaining challenges

A retrospective study of the yield of next‐generation sequencing in the diagnosis of developmental and epileptic encephalopathies and epileptic encephalopathies in 0–12 years aged children at a single tertiary care hospital in South India

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