Mining for mitochondrial mechanisms: Linking known syndromes to mitochondrial function

Abstract

Mitochondrial disorders (MDs) are caused by defects in 1 or multiple complexes of the oxidative phosphorylation (OXPHOS) machinery. MDs are associated with a broad range of clinical signs and symptoms, and have considerable clinical overlap with other neuromuscular syndromes. This overlap might be due to involvement of mitochondrial pathways in some of these non-mitochondrial syndromes. Here, we give an overview of around 25 non-mitochondrial syndromes, diagnosed in patients who were initially suspected to have a MD on the basis of clinical and biochemical parameters. In addition, we highlight the mitochondrial connections of 6 of these non-mitochondrial syndromes (eg, Rett syndrome and Dravet syndrome) diagnosed in multiple patients. Further research to unravel the interplay between these genes and mitochondria may help to increase knowledge on these syndromes. Additionally, it may open new avenues for research on pathways interacting with mitochondrial function in order to find new targets for therapeutics to treat MDs. The data presented in this review underline the importance of careful assessment of clinical, genetic, and biochemical data in all patients suspected of a neuromuscular syndrome, and highlights the importance of the role of clinical geneticists, physicians, and clinical biochemists in recognizing the possible mitochondrial connection of non-mitochondrial syndromes.

Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction

“…This often leads to a broadening of the clinical spectrum of known disorders. There is a growing number of disorders in which mitochondrial dysfunction is observed but the primary defect cannot be directly linked to known mitochondrial proteins or processes . The four patients described in this study presented with a multi‐system disorder including sensorimotor axonal peripheral neuropathy, myoclonic epilepsy which were highly suggestive for a mitochondrial disorder, even more so when taking the metabolic alterations in blood and urine into account (Table ).…”

Advancing genomic approaches to the molecular diagnosis of mitochondrial disease

“…If the pathogenic variant is missed, it is subsequently possible that a variant of uncertain significance (VUS) is incorrectly prioritized. Additionally, on a frequent basis, suspected mitochondriopathy patients are indeed not mitochondrial by genetic definition and would therefore inevitably evade detection by these panels [34].…”

“…Familial 'trio' sequencing facilitates phasing of haplotypes, the detection of de novo [47] and autosomal dominant variants, as well as aiding in variant prioritization by reducing the number of candidates by ten-fold when compared with sequencing the proband alone [48]. By querying exome-wide, the WES approach also enables the identification of non-mitochondrial genes presenting clinically as mitochondriopathy [34].…”

A new mechanism for cannabidiol in regulating the one‐carbon cycle and methionine levels in Dictyostelium and in mammalian epilepsy models

“…The cell and molecular basis of epilepsy and seizures is well-accepted to be related to electrical signalling and ion channel activity; however, a range of models have suggested that deregulation of several key amino acids is also involved in, or associated with, seizures and epilepsy (Bejarano & Rodriguez-navarro, 2015;Gupta et al, 2004). For example, numerous studies have proposed altered mitochondrial function in epilepsy pathology (Doccini et al, 2015;Kumar et al, 2016;Panneman, Smeitink, & Rodenburg, 2018;Pearson-smith, Liang, Rowley, Day, & Patel, 2017). Mitochondria contain the glycine cleavage system (GCS) that is responsible for regulation of glycine levels (Kikuchi & Hiraga, 1982) subsequently controlling numerous functions including protein synthesis and neurotransmission (Kolker, 2018).…”