Molecular basis of Leigh syndrome: a current look

Abstract

Leigh Syndrome (OMIM 256000) is a heterogeneous neurologic disorder due to damage in mitochondrial energy production that usually starts in early childhood. The first description given by Leigh pointed out neurological symptoms in children under 2 years and premature death. Following cases brought some hypothesis to explain the cause due to similarity to other neurological diseases and led to further investigation for metabolic diseases. Biochemical evaluation and specific metabolic profile suggested impairment in energy production (OXPHOS) in mitochondria. As direct approach to involved tissues is not always possible or safe, molecular analysis is a great cost-effective option and, besides biochemical results, is required to confirm the underlying cause of this syndrome face to clinical suspicion. The Next Generation Sequencing (NGS) advance represented a breakthrough in molecular biology allowing simultaneous gene analysis giving short-time results and increasing the variants underlying this syndrome, counting over 75 monogenic causes related so far. NGS provided confirmation of emerging cases and brought up diagnosis in atypical presentations as late-onset cases, which turned Leigh into a heterogeneous syndrome with variable outcomes. This review highlights clinical presentation in both classic and atypical phenotypes, the investigation pathway throughout confirmation emphasizing the underlying genetic heterogeneity and increasing number of genes assigned to this syndrome as well as available treatment.

Mitochondrial dysfunction in cardiovascular disease: Current status of translational research/clinical and therapeutic implications

“…Leigh syndrome or subacute necrotizing encephalopathy, is a neurodegenerative disease with broad phenotype and genotype presentations; >75 genes, encoded either by the mtDNA or the nDNA, have been reported to account for the disease 34 . The classical form has an early onset (<age 2), and presents with hypotonia, epilepsy, respiratory stress, neurodevelopmental delay, ataxia, and lactic acidosis; the late‐form has a more heterogeneous presentation, with behavioral/psychiatric manifestations, cognitive decline, movement disorders, headaches, or memory loss; it may even mimic multiple sclerosis 35 . Ataxia, ophthalmoplegia and CM seem to be more prevalent among patients with mtDNA defects 34 .…”

“…34 The classical form has an early onset (<age 2), and presents with hypotonia, epilepsy, respiratory stress, neurodevelopmental delay, ataxia, and lactic acidosis; the late-form has a more heterogeneous presentation, with behavioral/psychiatric manifestations, cognitive decline, movement disorders, headaches, or memory loss; it may even mimic multiple sclerosis. 35 Ataxia, ophthalmoplegia and CM seem to be more prevalent among patients with mtDNA defects. 34 Hypertrophic or dilated CM is reported in~10% of patients and is twice as prevalent in patients with mtDNA mutations compared with the nDNA group.…”

AC. elegansgenome-wide RNAi screen for altered levamisole sensitivity identifies genes required for muscle function

“…Our work shows that loss of epn-1 impacts postsynaptic function by having opposing effects on the abundance of postsynaptic L-AChRs and GABA A Rs. Notably, our screen also identified C. elegans homologs of genes mutated in congenital myasthenic syndrome (AChR), congenital muscular dystrophy (Mannose-1-phosphate guanyltransferase beta), congenital myopathy (Cofilin), myotonic dystrophy (ELAV-type RNA binding protein), and mitochondrial myopathy (NADH dehydrogenase) (Lu et al 1999;Milne and Hodgkin 1999;Agrawal et al 2007;Ockeloen et al 2012;Carss et al 2013;Engel et al 2015;Schubert and Vilarinho 2020). This suggests that altered response to levamisole can be used broadly to discover and study genes that impact muscle function.…”

Novel NDUFA13 Mutations Associated with OXPHOS Deficiency and Leigh Syndrome: A Second Family Report

“…Although some results from OXPHOS functionality experiments were similar in both families, we particularly found very reduced levels of the NDUFA13 protein in the patient's fibroblasts (90% of control), while the first family had a less severe decrease (mean reduction in both sisters was 70% of control). Alternatively, factors other than OXPHOS dysfunction may influence the differential phenotype expression [38]. Our results from SC assembly studies in cultured fibroblasts are similar to those found in the first family reported (i.e., loss of CI stability and diminished formation of the respirasome [I+III 2 +IV 1-2 ]), which supports that the NDUFA13 protein might play a critical role in the assembly or stability of the respirasomes, as previously shown in NDUFA13 knockout HEK293T cells [39].…”