Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: Is riboflavin supplementation effective?

Background: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. Results: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and

Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome

Leigh syndrome (LS) is a severe manifestation of mitochondrial disease in children and is currently incurable. The lack of effective models hampers our understanding of the mechanisms underlying the neuronal pathology of LS. Using patient-derived induced pluripotent stem cells and CRISPR/Cas9 engineering, we developed a human model of LS caused by mutations in the complex IV assembly gene SURF1. Single-cell RNA-sequencing and multi-omics analysis revealed compromised neuronal morphogenesis in mutant neural cultures and brain organoids. The defects emerged at the level of neural progenitor cells (NPCs), which retained a glycolytic proliferative state that failed to instruct neuronal morphogenesis. LS NPCs carrying mutations in the complex I gene NDUFS4 recapitulated morphogenesis defects. SURF1 gene augmentation and PGC1A induction via bezafibrate treatment supported the metabolic programming of LS NPCs, leading to restored neuronal morphogenesis. Our findings provide mechanistic insights and suggest potential interventional strategies for a rare mitochondrial disease

MEGDEL Syndrome: Expanding the Phenotype and New Mutations

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Leucine Loading Test is Only Discriminative for 3-Methylglutaconic Aciduria Due to AUH Defect

Item does not contain fulltextCurrently, six inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature are known. The "Primary 3-methylglutaconic aciduria," 3-methylglutaconyl-CoA hydratase deficiency or AUH defect, is a disorder of leucine catabolism. For all other subtypes, also denoted "Secondary 3-methylglutaconic acidurias" (TAZ defect or Barth syndrome, SERAC1 defect or MEGDEL syndrome, OPA3 defect or Costeff syndrome, DNAJC19 defect or DCMA syndrome, TMEM70 defect, "not otherwise specified (NOS) 3-MGA-uria"), the origin of 3-methylglutaconic aciduria remains enigmatic but is hypothesized to be independent from leucine catabolism. Here we show the results of leucine loading test in 21 patients with different inborn errors of metabolism who present with 3-methylglutaconic aciduria. After leucine loading urinary 3-methylglutaconic acid levels increased only in the patients with an AUH defect. This strongly supports the hypothesis that 3-methylglutaconic aciduria is independent from leucine breakdown in other inborn errors of metabolism with 3-methylglutaconic aciduria and also provides a simple test to discriminate between primary and secondary 3-methylglutaconic aciduria in regular patient care

Developing outcome measures for pediatric mitochondrial disorders: which complaints and limitations are most burdensome to patients and their parents?

Item does not contain fulltextSince some drug intervention effects are only experienced by the patient, organizations such as the Food and Drug Administration prefer clinically meaningful outcome measures. Here, we evaluated which symptoms and limitations in daily life are most burdensome to pediatric patients with mitochondrial disorders and their parents, using two questionnaires. In a study of 78 patients, the most burdensome complaints included fatigue, behavior and speech disturbances, epilepsy and muscle weakness and a high degree of limitations in daily activities was found. Importantly, there was a discrepancy between what symptoms metabolic pediatricians estimated would be most burdensome compared to the patients'/caretakers' opinion. To include feasible and relevant outcome measures in intervention studies, the experience and opinions of patients and caretakers should therefore be heard.1 januari 201

Mitochondrial Disease and Hearing Loss in Children: A Systematic Review

OBJECTIVES: Hearing loss is a clinical symptom, frequently mentioned in the context of mitochondrial disease. With no cure available for mitochondrial disease, supportive treatment of clinical symptoms like hearing loss is of the utmost importance. The aim of this study was to summarize current knowledge on hearing loss in genetically proven mitochondrial disease in children and deduce possible and necessary consequences in patient care. METHODS: Systematic literature review, including Medline, Embase, and Cochrane library. Review protocol was established and registered prior to conduction (International prospective register of systematic reviews-PROSPERO: CRD42020165356). Conduction of this review was done in accordance with MOOSE criteria. RESULTS: A total of 23 articles, meeting predefined criteria and providing sufficient information on 75 individuals with childhood onset hearing loss was included for analysis. Both cochlear and retro-cochlear origin of hearing loss can be identified among different types of mitochondrial disease. Analysis was hindered by inhomogeneous reporting and methodical limitations. CONCLUSION: Overall, the findings do not allow for a general statement on hearing loss in children with mitochondrial disease. Retro-cochlear hearing loss seems to be found more often than expected. A common feature appears to be progression of hearing loss over time. However, hearing loss in these patients shows manifold characteristics. Therefore, awareness of mitochondrial disease as a possible causative background is important for otolaryngologists. Future attempts rely on standardized reporting and long-term follow-up. LEVEL OF EVIDENCE: NA Laryngoscope, 132:2459-2472, 2022

CLPB (caseinolytic peptidase B homolog), the first mitochondrial protein refoldase associated with human disease.

Contains fulltext : 219662.pdf (Publisher’s version ) (Open Access

Corrigendum to “Lifetime risk of autosomal recessive mitochondrial disorders calculated from genetic databases” [EBioMedicine 54 (2020) 102730] (EBioMedicine (2020) 54, (S2352396420301055), (10.1016/j.ebiom.2020.102730)).

The authors regret that the published manuscript contains a few rounding and copying errors. The mistakes are minor but affect the allele frequencies of disease-causing variants in 3 genes. These minor corrections do not change the overall description, interpretation, or conclusions of the manuscript. page 4, paragraph 3.1., 2nd sentence: The sum of their allele frequencies was 0.0111 in the European (Non-Finnish) and 0.0091 in the total gnomAD dataset resulting in a calculated PKU lifetime risk of 16.0 (14.5–17.6 95% CI)/100,000 in the European (Non-Finnish) population and of 8.2 (7.6–8.9)/100,000 in the total dataset. is corrected to The sum of their allele frequencies was 0.0126 in the European (Non-Finnish) and 0.0091 in the total gnomAD dataset resulting in a calculated PKU lifetime risk of 16.0 (14.5–17.6 95% CI)/100,000 in the European (Non-Finnish) population and of 8.2 (7.6–8.9)/100,000 in the total dataset. page 4, paragraph 3.2., close to the end of 3rd paragraph The allele frequency of POLG mutations was 0.0083 in the European (Non-Finnish) gnomAD dataset, 0.0061 in the total gnomAD dataset and 0.0074 in the in-house database, resulting in lifetime risk estimates for POLG-associated disorders of 6.9 (6.1–7.8), 3.7 (3.4–4.0) and 3.7 (3.3–4.1)/100,000, respectively. is corrected to The allele frequency of POLG mutations was 0.0083 in the European (Non-Finnish) gnomAD dataset, 0.0061 in the total gnomAD dataset and 0.0061 in the in-house database, resulting in lifetime risk estimates for POLG-associated disorders of 6.9 (6.1–7.8), 3.7 (3.4–4.0) and 3.7 (3.3–4.1)/100,000, respectively. page 6, right column, line 4–6 Implying a combined frequency of 0.0083, and leading to a calculated MCADD lifetime risk of 4.8 (3.6–6.3)/100,000. is corrected to Implying a combined frequency of 0.0069, and leading to a calculated MCADD lifetime risk of 4.8 (3.6–6.3)/100,000. In addition, the Author Contribution section was accidentally omitted due to a production error. This reads: MW and TK conceived the study. JT and MW defined a comprehensive list of mitochondrial disease genes and set up a list of pathogenic variants in these genes, supported by SLS, TMS, and SBW. JT and MW queried two databases (gnomAD and in house) to assess the allele frequencies of disease-causing variants in the general population and calculated the lifetime risks, supported by HP, TM, KO and TK. JT and MW drafted the manuscript which was then refined by all other authors and finalized by MW and TK