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Viruses that are typically benign sometimes invade the brainstem in otherwise healthy children. We report bi-allelic DBR1 mutations in unrelated patients from different ethnicities, each of whom had brainstem infection due to herpes simplex virus 1 (HSV1), influenza virus, or norovirus. DBR1 encodes the only known RNA lariat debranching enzyme. We show that DBR1 expression is ubiquitous, but strongest in the spinal cord and brainstem. We also show that all DBR1 mutant alleles are severely hypomorphic, in terms of expression and function. The fibroblasts of DBR1-mutated patients contain higher RNA lariat levels than control cells, this difference becoming even more marked during HSV1 infection. Finally, we show that the patients' fibroblasts are highly susceptible to HSV1. RNA lariat accumulation and viral susceptibility are rescued by wild-type DBR1. Autosomal recessive, partial DBR1 deficiency underlies viral infection of the brainstem in humans through the disruption of tissue-specific and cell-intrinsic immunity to viruses.
Neonatal seizures (NS) occur in the first 28 days of life; they represent an important emergency that requires a rapid diagnostic work-up to start a prompt therapy. The most common causes of NS include: intraventricular haemorrhage, hypoxic-ischemic encephalopathy, hypoglycemia, electrolyte imbalance, neonatal stroke or central nervous system infection. Nevertheless, an Inborn Error of Metabolism (IEM) should be suspected in case of NS especially if these are resistant to common antiseizure drugs (ASDs) and with metabolic decompensation. Nowadays, Expanded Newborn Screening (ENS) has changed the natural history of some IEMs allowing a rapid diagnosis and a prompt onset of specific therapy; nevertheless, not all IEMs are detected by such screening (e.g. Molybdenum-Cofactor Deficiency, Hypophosphatasia, GLUT1-Deficiency Syndrome) and for this reason neonatologists have to screen for these diseases in the diagnostic work-up of NS. For IEMs, there are not specific semiology of seizures and EEG patterns. Herein, we report a systematic review on those IEMs that lead to NS and epilepsy in the neonatal period, studying only those IEMs not included in the ENS with tandem mass, suggesting clinical, biochemical features, and diagnostic work-up. Remarkably, we have observed a worse neurological outcome in infants undergoing only a treatment with common AED for their seizures, in comparison to those primarily treated with specific anti-convulsant treatment for the underlying metabolic disease (e.g.Ketogenic Diet, B6 vitamin). For this reason, we underline the importance of an early diagnosis in order to promptly intervene with a targeted treatment without waiting for drug resistance to arise.
Metachromatic leukodystrophy (MLD) is a human neurodegenerative disorder characterized by progressive damage on the myelin band in the nervous system. MLD is caused by the impaired function of the lysosomal enzyme Arylsulphatase A (ARSA). The physiopathology mechanisms and the biochemical consequences in the brain of ARSA deficiency are not entirely understood. In recent years, the use of genome-scale metabolic (GEM) models has been explored as a tool for the study of the biochemical alterations in MLD. Previously, we modeled the metabolic consequences of different lysosomal storage diseases using single GEMs. In the case of MLD, using a glia GEM, we previously predicted that the metabolism of glycosphingolipids and neurotransmitters was altered. The results also suggested that mitochondrial metabolism and amino acid transport were the main reactions affected. In this study, we extended the modeling of the metabolic consequences of ARSA deficiency through the integration of neuron and glial cell metabolic models. Cell-specific models were generated from Recon2, and these were used to create a neuron-glial bi-cellular model. We propose a workflow for the integration of this type of model and its subsequent study. The results predicted the impairment pathways involved in the transport of amino acids, lipids metabolism, and catabolism of purines and pyrimidines. The use of this neuron-glial GEM metabolic reconstruction allowed to improve the prediction capacity of the metabolic consequences of ARSA deficiency, which might pave the way for the modeling of the biochemical alterations of other inborn errors of metabolism with central nervous system involvement.
Global metabolomic profiling offers novel opportunities for the discovery of biomarkers and for the elucidation of pathogenic mechanisms that might lead to the development of novel therapies. GLUT1 deficiency syndrome (GLUT1-DS) is an inborn error of metabolism due to reduced function of glucose transporter type 1. Clinical presentation of GLUT1-DS is heterogeneous and the disorder mirrors patients with epilepsy, movement disorders, or any paroxysmal events or unexplained neurological manifestation triggered by exercise or fasting. The diagnostic biochemical hallmark of the disease is a reduced cerebrospinal fluid (CSF)/blood glucose ratio and the only available treatment is ketogenic diet. This study aimed at advancing our understanding of the biochemical perturbations in GLUT1-DS pathogenesis through biochemical phenotyping and the treatment of GLUT1-DS with a ketogenic diet. Metabolomic analysis of three CSF samples from GLUT1-DS patients not on ketogenic diet was feasible inasmuch as CSF sampling was used for diagnosis before to start with ketogenic diet. The analysis of plasma and urine samples obtained from GLUT1-DS patients treated with a ketogenic diet showed alterations in lipid and amino acid profiles. While subtle, these were consistent findings across the patients with GLUT1-DS on ketogenic diet, suggesting impacts on mitochondrial physiology. Moreover, low levels of free carnitine were present suggesting its consumption in GLUT1-DS on ketogenic diet. 3-hydroxybutyrate, 3-hydroxybutyrylcarnitine, 3-methyladipate, and N-acetylglycine were identified as potential biomarkers of GLUT1-DS on ketogenic diet. This is the first study to identify CSF, plasma, and urine metabolites associated with GLUT1-DS, as well as biochemical changes impacted by a ketogenic diet. Potential biomarkers and metabolic insights deserve further investigation.
Here we report, for the first time, the engineering of human red blood cells (RBCs) with an entire metabolic pathway as a potential strategy to treat patients with guanidinoacetate methyltransferase (GAMT) deficiency, capable of reducing the high toxic levels of guanidinoacetate acid (GAA) and restoring proper creatine levels in blood and tissues. We first produced a recombinant form of native human GAMT without any tags to encapsulate into RBCs. Due to the poor solubility and stability features of the recombinant enzyme, both bioinformatics studies and extensive optimization work were performed to select a mutant GAMT enzyme, where only four critical residues were replaced, as a lead candidate. However, GAMT-loaded RBCs were ineffective in GAA consumption and creatine production because of the limiting intra-erythrocytic S-adenosyl methionine (SAM) content unable to support GAMT activity. Therefore, a recombinant form of human methionine adenosyl transferase (MAT) was developed. RBCs co-entrapped with both GAMT and MAT enzymes performed, in vitro, as a competent cellular bioreactor to remove GAA and produce creatine, fueled by physiological concentrations of methionine and the ATP generated by glycolysis. Our results highlight that metabolic engineering of RBCs is possible and represents proof of concept for the design of novel therapeutic approaches.
Creatine (Cr) is a small metabolite with a central role in energy metabolism and mitochondrial function. Creatine deficiency syndromes are inborn errors of Cr metabolism causing Cr depletion in all body tissues and particularly in the nervous system. Patient symptoms involve intellectual disability, language and behavioral disturbances, seizures and movement disorders suggesting that brain cells are particularly sensitive to Cr depletion. Cr deficiency was found to affect metabolic activity and structural abnormalities of mitochondrial organelles; however a detailed analysis of molecular mechanisms linking Cr deficit, energy metabolism alterations and brain dysfunction is still missing. Using a proteomic approach we evaluated the proteome changes of the brain mitochondrial fraction induced by the deletion of the Cr transporter (CrT) in developing mutant mice. We found a marked alteration of the mitochondrial proteomic landscape in the brain of CrT deficient mice, with the overexpression of many proteins involved in energy metabolism and response to oxidative stress. Moreover, our data suggest possible abnormalities of dendritic spines, synaptic function and plasticity, network excitability and neuroinflammatory response. Intriguingly, the alterations occurred in coincidence with the developmental onset of neurological symptoms. Thus, cerebral mitochondrial alterations could represent an early response to Cr deficiency that could be targeted for therapeutic intervention.
Exome sequencing (ES) in the clinical setting of inborn metabolic diseases (IMDs) has created tremendous improvement in achieving an accurate and timely molecular diagnosis for a greater number of patients, but it still leaves the majority of patients without a diagnosis. In parallel, (personalized) treatment strategies are increasingly available, but this requires the availability of a molecular diagnosis. IMDs comprise an expanding field with the ongoing identification of novel disease genes and the recognition of multiple inheritance patterns, mosaicism, variable penetrance, and expressivity for known disease genes. The analysis of trio ES is preferred over singleton ES as information on the allelic origin (paternal, maternal, "de novo") reduces the number of variants that require interpretation. All ES data and interpretation strategies should be exploited including CNV and mitochondrial DNA analysis. The constant advancements in available techniques and knowledge necessitate the close exchange of clinicians and molecular geneticists about genotypes and phenotypes, as well as knowledge of the challenges and pitfalls of ES to initiate proper further diagnostic steps. Functional analyses (transcriptomics, proteomics, and metabolomics) can be applied to characterize and validate the impact of identified variants, or to guide the genomic search for a diagnosis in unsolved cases. Future diagnostic techniques (genome sequencing [GS], optical genome mapping, long-read sequencing, and epigenetic profiling) will further enhance the diagnostic yield. We provide an overview of the challenges and limitations inherent to ES followed by an outline of solutions and a clinical checklist, focused on establishing a diagnosis to eventually achieve (personalized) treatment.
X-linked adrenoleukodystrophy (ALD), a progressive neurodegenerative disease, is caused by mutations in ABCD1 and characterized by very-long-chain fatty acids (VLCFA) accumulation. Virtually all males develop progressive myelopathy (AMN). A subset of patients, however, develops a fatal cerebral demyelinating disease (cerebral ALD). Hematopoietic stem cell transplantation is curative for cerebral ALD provided the procedure is performed in an early stage of the disease. Unfortunately, this narrow therapeutic window is often missed. Therefore, an increasing number of newborn screening programs are including ALD. To identify new biomarkers for ALD, we developed an Abcd1 knockout mouse with enhanced VLCFA synthesis either ubiquitous or restricted to oligodendrocytes. Biochemical analysis revealed VLCFA accumulation in different lipid classes and acylcarnitines. Both C26:0-lysoPC and C26:0-carnitine were highly elevated in brain, spinal cord, but also in bloodspots. We extended the analysis to patients and confirmed that C26:0-carnitine is also elevated in bloodspots from ALD patients. We anticipate that validation of C26:0-carnitine for the diagnosis of ALD in newborn bloodspots may lead to a faster inclusion of ALD in newborn screening programs in countries that already screen for other inborn errors of metabolism.
Classical Galactosemia (CG) is an inherited disorder of galactose metabolism caused by a deficiency of the galactose-1-phosphate uridylyltransferase (GALT) enzyme resulting in neurocognitive complications. As in many Inborn Errors of Metabolism, the metabolic pathway of CG is well-defined, but the pathophysiology and high variability in clinical outcome are poorly understood. The aim of this study was to investigate structural changes of the brain of CG patients on MRI and their association with clinical outcome.
Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. If left untreated, PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. PKU management differs widely across Europe and therefore these guidelines have been developed aiming to optimize and standardize PKU care. Professionals from 10 different European countries developed the guidelines according to the AGREE (Appraisal of Guidelines for Research and Evaluation) method. Literature search, critical appraisal and evidence grading were conducted according to the SIGN (Scottish Intercollegiate Guidelines Network) method. The Delphi-method was used when there was no or little evidence available. External consultants reviewed the guidelines. Using these methods 70 statements were formulated based on the highest quality evidence available. The level of evidence of most recommendations is C or D. Although study designs and patient numbers are sub-optimal, many statements are convincing, important and relevant. In addition, knowledge gaps are identified which require further research in order to direct better care for the future.
In the last years, lysosomal storage diseases appear as a bridge of knowledge between rare genetic inborn metabolic disorders and neurodegenerative diseases such as Parkinson's disease (PD) or frontotemporal dementia. Epidemiological studies helped promote research in the field that continues to improve our understanding of the link between mutations in the glucocerebrosidase (GBA) gene and PD. We conducted a review of this link, highlighting the association in GBA mutation carriers and in Gaucher disease type 1 patients (GD type 1). A comprehensive review of the literature from January 2008 to December 2018 was undertaken. Relevance findings include: (1) There is a bidirectional interaction between GBA and α- synuclein in protein homeostasis regulatory pathways involving the clearance of aggregated proteins. (2) The link between GBA deficiency and PD appears not to be restricted to α⁻synuclein aggregates but also involves Parkin and PINK1 mutations. (3) Other factors help explain this association, including early and later endosomes and the lysosomal-associated membrane protein 2A (LAMP-2A) involved in the chaperone-mediated autophagy (CMA). (4) The best knowledge allows researchers to explore new therapeutic pathways alongside substrate reduction or enzyme replacement therapies.
Sjögren-Larsson syndrome (SLS) is a rare inborn error of lipid metabolism. The syndrome is caused by mutations in the ALDH3A2 gene, resulting in a deficiency of fatty aldehyde dehydrogenase. Most patients have a clearly recognizable severe phenotype, with congenital ichthyosis, intellectual disability, and spastic diplegia. In this study, we describe two patients with a remarkably mild phenotype. In both patients, males with actual ages of 45 and 61 years, the diagnosis was only established at an adult age. Their skin had been moderately affected from childhood onward, and both men remained ambulant with mild spasticity of their legs. Cognitive development, as reflected by school performance and professional career, had been unremarkable. Magnetic resonance spectroscopy of the first patient was lacking the characteristic lipid peak. We performed a literature search to identify additional SLS patients with a mild phenotype. We compared the clinical, radiologic, and molecular features of the mildly affected patients with the classical phenotype. We found 10 cases in the literature with a molecular proven diagnosis and a mild phenotype. Neither a genotype-phenotype correlation nor an alternative explanation for the strikingly mild phenotypes was found. New biochemical techniques to study the underlying metabolic defect in SLS, like lipidomics, may in the future help to unravel the reasons for the exceptionally mild phenotypes. In the meantime, it is important to recognize these mildly affected patients to provide them with appropriate care and genetic counseling, and to increase our insights in the true disease spectrum of SLS.
Cobalamin C (cblC) deficiency is the most common inborn error of intracellular cobalamin metabolism caused by pathogenic variant(s) in MMACHC and manifests with methylmalonic acidemia, hyperhomocysteinemia, and hypomethioninemia with a variable age of presentation. Individuals with late-onset cblC may be asymptomatic until manifesting neuropsychiatric symptoms, thromboembolic events, and renal disease. Although hydroxocobalamin provides a foundation for therapy, optimal dose regimen for adult patients has not been systematically evaluated. We report three adult siblings with late-onset cblC disease, and their biochemical and clinical responses to high-dose hydroxocobalamin. The 28-year-old proband presented with severe psychosis, progressive neurological deterioration, and deep venous thrombosis complicated by a pulmonary embolism. MRI studies identified lesions in the spinal cord, periventricular white matter, and basal ganglia. Serum homocysteine and methylmalonic acid levels were markedly elevated. Hydroxocobalamin at standard dose (1 mg/day) initially resulted in partial metabolic correction. A regimen of high-dose hydroxocobalamin (25 mg/day) together with betaine and folic acid resulted in rapid and sustainable biochemical correction, resolution of psychosis, improvement of neurological functions, and amelioration of brain and spinal cord lesions. Two siblings who did not manifest neuropsychiatric symptoms or thromboembolism achieved a satisfactory metabolic control with the same high-dose regimen. Hydroxocobalamin injection was then spaced out to 25 mg weekly with good and sustainable metabolic control. All three patients are compound heterozygotes for c.271dupA p.Arg91LysfsX14 and c.389A > G p.Tyr130Cys. This study highlights the importance of evaluating intracellular cobalamin metabolism in adults with neuropsychiatric manifestations and/or thromboembolic events, and demonstrates that high-dose hydroxocobalamin achieves rapid and sustainable metabolic control and improvement in neuropsychiatric outcomes in adults with late-onset cblC disease.
Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, functions as a cofactor in humans for more than 140 enzymes, many of which are involved in neurotransmitter synthesis and degradation. A deficiency of PLP can present, therefore, as seizures and other symptoms that are treatable with PLP and/or pyridoxine. Deficiency of PLP in the brain can be caused by inborn errors affecting B6 vitamer metabolism or by inactivation of PLP, which can occur when compounds accumulate as a result of inborn errors of other pathways or when small molecules are ingested. Whole-exome sequencing of two children from a consanguineous family with pyridoxine-dependent epilepsy revealed a homozygous nonsense mutation in proline synthetase co-transcribed homolog (bacterial), PROSC, which encodes a PLP-binding protein of hitherto unknown function. Subsequent sequencing of 29 unrelated indivduals with pyridoxine-responsive epilepsy identified four additional children with biallelic PROSC mutations. Pre-treatment cerebrospinal fluid samples showed low PLP concentrations and evidence of reduced activity of PLP-dependent enzymes. However, cultured fibroblasts showed excessive PLP accumulation. An E.coli mutant lacking the PROSC homolog (ΔYggS) is pyridoxine sensitive; complementation with human PROSC restored growth whereas hPROSC encoding p.Leu175Pro, p.Arg241Gln, and p.Ser78Ter did not. PLP, a highly reactive aldehyde, poses a problem for cells, which is how to supply enough PLP for apoenzymes while maintaining free PLP concentrations low enough to avoid unwanted reactions with other important cellular nucleophiles. Although the mechanism involved is not fully understood, our studies suggest that PROSC is involved in intracellular homeostatic regulation of PLP, supplying this cofactor to apoenzymes while minimizing any toxic side reactions.
Asparagine synthetase deficiency (ASNSD, OMIM #615574) is a rare autosomal recessive neurometabolic inborn error that leads to severe cognitive impairment. It manifests with microcephaly, intractable seizures, and progressive cerebral atrophy. Currently, there is no established treatment for this condition. In our pediatric cohort, we discovered, by whole-exome sequencing in two siblings from Turkey, a novel homozygous missense mutation in asparagine synthetase at NM_133436.3 (ASNS_v001): c.1108C>T that results in an amino acid exchange p.(Leu370Phe), in the C-terminal domain. After identification of the metabolic defect, treatment with oral asparagine supplementation was attempted in both patients for 24 months. Asparagine supplementation was well tolerated, and no further disease progression was observed during treatment. One of our patients showed mild developmental progress with increased levels of attention and improved nonverbal communication. These results support our hypothesis that asparagine supplementation should be further investigated as a treatment option for ASNSD. We further reviewed all previously reported ASNSD cases with regard for their clinical phenotypes and brain imaging findings to provide an essential knowledge base for rapid diagnosis and future clinical studies.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder which primarily affects the gastrointestinal and nervous systems. This disease is caused by mutations in the nuclear TYMP gene, which encodes for thymidine phosphorylase, an enzyme required for the normal metabolism of deoxynucleosides, thymidine, and deoxyuridine. The subsequent elevated systemic concentrations of deoxynucleosides lead to increased intracellular concentrations of their corresponding triphosphates, and ultimately mitochondrial failure due to progressive accumulation of mitochondrial DNA (mtDNA) defects and mtDNA depletion. Currently, there are no treatments for MNGIE where effectiveness has been evidenced in clinical trials. This Phase 2, multi-centre, multiple dose, open label trial without a control will investigate the application of erythrocyte-encapsulated thymidine phosphorylase (EE-TP) as an enzyme replacement therapy for MNGIE. Three EE-TP dose levels are planned with patients receiving the dose level that achieves metabolic correction. The study duration is 31 months, comprising 28 days of screening, 90 days of run-in, 24 months of treatment and 90 days of post-dose follow-up. The primary objectives are to determine the safety, tolerability, pharmacodynamics, and efficacy of multiple doses of EE-TP. The secondary objectives are to assess EE-TP immunogenicity after multiple dose administrations and changes in clinical assessments, and the pharmacodynamics effect of EE-TP on clinical assessments.
Alzheimer's disease (AD) is a neurodegenerative disorder, accounting for at least two-thirds of dementia cases. A combination of genetic, epigenetic and environmental triggers is widely accepted to be responsible for the onset and development of AD. Accumulating evidence shows that oxidative stress and dysregulation of energy metabolism play an important role in AD pathogenesis, leading to neuronal dysfunction and death. Redox-induced protein modifications have been reported in the brain of AD patients, indicating excessive oxidative damage. Coenzyme A (CoA) is essential for diverse metabolic pathways, regulation of gene expression and biosynthesis of neurotransmitters. Dysregulation of CoA biosynthesis in animal models and inborn mutations in human genes involved in the CoA biosynthetic pathway have been associated with neurodegeneration. Recent studies have uncovered the antioxidant function of CoA, involving covalent protein modification by this cofactor (CoAlation) in cellular response to oxidative or metabolic stress. Protein CoAlation has been shown to both modulate the activity of modified proteins and protect cysteine residues from irreversible overoxidation. In this study, immunohistochemistry analysis with highly specific anti-CoA monoclonal antibody was used to reveal protein CoAlation across numerous neurodegenerative diseases, which appeared particularly frequent in AD. Furthermore, protein CoAlation consistently co-localized with tau-positive neurofibrillary tangles, underpinning one of the key pathological hallmarks of AD. Double immunihistochemical staining with tau and CoA antibodies in AD brain tissue revealed co-localization of the two immunoreactive signals. Further, recombinant 2N3R and 2N4R tau isoforms were found to be CoAlated in vitro and the site of CoAlation mapped by mass spectrometry to conserved cysteine 322, located in the microtubule binding region. We also report the reversible H2O2-induced dimerization of recombinant 2N3R, which is inhibited by CoAlation. Moreover, CoAlation of transiently expressed 2N4R tau was observed in diamide-treated HEK293/Pank1β cells. Taken together, this study demonstrates for the first time extensive anti-CoA immunoreactivity in AD brain samples, which occurs in structures resembling neurofibrillary tangles and neuropil threads. Covalent modification of recombinant tau at cysteine 322 suggests that CoAlation may play an important role in protecting redox-sensitive tau cysteine from irreversible overoxidation and may modulate its acetyltransferase activity and functional interactions.
Hypomyelinating leukodystrophies are genetic disorders characterized by insufficient myelin deposition during development. They are diagnosed on the basis of both clinical and MRI features followed by genetic confirmation. Here, we report on four unrelated affected individuals with hypomyelination and bi-allelic pathogenic variants in EPRS, the gene encoding cytoplasmic glutamyl-prolyl-aminoacyl-tRNA synthetase. EPRS is a bifunctional aminoacyl-tRNA synthetase that catalyzes the aminoacylation of glutamic acid and proline tRNA species. It is a subunit of a large multisynthetase complex composed of eight aminoacyl-tRNA synthetases and its three interacting proteins. In total, five different EPRS mutations were identified. The p.Pro1115Arg variation did not affect the assembly of the multisynthetase complex (MSC) as monitored by affinity purification-mass spectrometry. However, immunoblot analyses on protein extracts from fibroblasts of the two affected individuals sharing the p.Pro1115Arg variant showed reduced EPRS amounts. EPRS activity was reduced in one affected individual's lymphoblasts and in a purified recombinant protein model. Interestingly, two other cytoplasmic aminoacyl-tRNA synthetases have previously been implicated in hypomyelinating leukodystrophies bearing clinical and radiological similarities to those in the individuals we studied. We therefore hypothesized that leukodystrophies caused by mutations in genes encoding cytoplasmic aminoacyl-tRNA synthetases share a common underlying mechanism, such as reduced protein availability, abnormal assembly of the multisynthetase complex, and/or abnormal aminoacylation, all resulting in reduced translation capacity and insufficient myelin deposition in the developing brain.
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.
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