RESUMEN
BACKGROUND: Pathogenic variants in the NDUFV1 gene disrupt mitochondrial complex I, leading to neuroregression with leukoencephalopathy and basal ganglia involvement on neuroimaging. This study aims to provide a concise review on NDUFV1-related disorders while adding the largest cohort from a single center to the existing literature. METHODS: We retrospectively collected genetically proven cases of NDUFV1 pathogenic variants from our center over the last decade and explored reported instances in existing literature. Magnetic resonance imaging (MRI) patterns observed in these patients were split into three types-Leigh (putamen, basal ganglia, thalamus, and brainstem involvement), mitochondrial leukodystrophy (ML) (cerebral white matter involvement with cystic cavitations), and mixed (both). RESULTS: Analysis included 44 children (seven from our center and 37 from literature). The most prevalent comorbidities were hypertonia, ocular abnormalities, feeding issues, and hypotonia at onset. Children with the Leigh-type MRI pattern exhibited significantly higher rates of breathing difficulties, whereas those with a mixed phenotype had a higher prevalence of dystonia. The c.1156C>T variant in exon 8 of the NDUFV1 gene was the most common variant among individuals of Asian ethnicity and is predominantly associated with irritability and dystonia. Seizures and Leigh pattern of MRI of the brain was found to be less commonly associated with this variant. Higher rate of mortality was observed in children with Leigh-type pattern on brain MRI and those who did not receive mitochondrial cocktail. CONCLUSIONS: MRI phenotyping might help predict outcome. Appropriate and timely treatment with mitochondrial cocktail may reduce the probability of death and may positively impact the long-term outcomes, regardless of the genetic variant or age of onset.
Asunto(s)
Complejo I de Transporte de Electrón , Enfermedades Mitocondriales , NADH Deshidrogenasa , Humanos , Estudios Retrospectivos , Masculino , Complejo I de Transporte de Electrón/genética , Femenino , Preescolar , Lactante , Niño , NADH Deshidrogenasa/genética , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/diagnóstico por imagen , Imagen por Resonancia Magnética , Enfermedad de Leigh/genética , Enfermedad de Leigh/diagnóstico por imagen , AdolescenteRESUMEN
HISTORY: A 9-month-old preterm male infant born at 33 weeks gestation presented with a 2-month history of developmental decline. The parents reported that over the past several months, they noted regression of milestones, where the infant stopped smiling, crying, expressing himself, or making eye contact. The parents also reported that the infant had multiple seizures during which he would wake up stiff and stare into space for 10-20 seconds while his lips would become blue. The parents were referred to a neurologist, where physical examination was notable for hypotonia. Electroencephalography (EEG) revealed frequent bilateral parietal epileptiform discharges. The patient was subsequently started on lacosamide. The patient's medical history was notable for abnormally low citrulline levels at birth, with negative results of urea cycle disorder testing at the time, along with left inguinal hernia repair performed 3 months ago. More recent laboratory analysis had shown persistently elevated serum lactate and alanine levels. There was no history of travel, recent infection, or vaccine administration. MRI of the brain with spectroscopy was performed for further evaluation.
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Enfermedad de Leigh , Recién Nacido , Lactante , Humanos , Masculino , Enfermedad de Leigh/diagnóstico por imagen , Encéfalo , Electroencefalografía , Recien Nacido Prematuro , LacosamidaRESUMEN
Background: Leigh syndrome (LS) is a progressive neurodegenerative disorder of infancy/early childhood secondary to mitochondrial dysfunction. Imaging plays a pivotal role in the diagnosis of LS with certain typical magnetic resonance imaging (MRI) findings considered as a part of diagnostic criteria. We appraised various MRI findings on conventional MRI sequences and also assessed potential correlation between diffusion abnormalities and patient's clinical presentation. Aims: Our aim was to describe various patterns of central nervous system involvement in LS and to assess the correlation of diffusion-weighted imaging abnormalities with clinical presentation. Settings and Design: The design of the study was retrospective comprising 8 children with LS who had MRI between years 2014 and 2019. Subjects and Methods: Eight children between the age group of 4 months 8 years with LS based on clinical presentation, elevated lactate levels in CSF/Blood, and typical MRI findings were included in the study. Results and Conclusions: Brainstem was involved all (100%) patients while basal ganglia was affected in 5 (62.5%) children. Cerebral white matter involvement was present in 3 (37.5%) children, cerebellar in 2 (25%) children while spinal, corpus callosum, and thalamic involvement were observed in one (12.5%) patient each. Diffusion restriction was observed in 6 children, all of them presented with altered sensorium. Conventional MRI serves as an excellent tool for the diagnosis of LS in children with clinical suspicion. Acute encephalopathy frequently presents with diffusion restriction corresponding to active lesions. Hence, diffusion restriction on MRI predicts the activity of lesions in patients with LS.
Résumé Contexte: Le syndrome de Leigh (LS) est une maladie neurodégénérative progressive de la petite enfance/petite enfance secondaire à des maladies mitochondriales. dysfonctionnement. L'imagerie joue un rôle central dans le diagnostic du LS, certains résultats typiques de l'imagerie par résonance magnétique (IRM) étant considérés comme une partie des critères diagnostiques. Nous avons évalué divers résultats d'IRM sur des séquences d'IRM conventionnelles et également évalué la corrélation potentielle entre anomalies de diffusion et présentation clinique du patient. Objectifs: Notre objectif était de décrire divers modèles d'atteinte du système nerveux central dans le LS et pour évaluer la corrélation des anomalies d'imagerie pondérées en diffusion avec la présentation clinique. Paramètres et conception: la conception de l'étude était rétrospective comprenant 8 enfants atteints de LS qui ont eu une IRM entre les années 2014 et 2019. Sujets et méthodes: Huit enfants entre le groupe d'âge de 4 mois 8 ans avec LS basé sur la présentation clinique, les niveaux élevés de lactate dans le LCR/le sang, et typique Les résultats de l'IRM ont été inclus dans l'étude. Résultats et conclusions : Le tronc cérébral a été impliqué chez tous les patients (100 %) tandis que les ganglions de la base ont été impliqués. touché chez 5 (62,5%) enfants. Une atteinte cérébrale de la substance blanche était présente chez 3 (37,5%) enfants, cérébelleuse chez 2 (25%) enfants alors que Une atteinte de la colonne vertébrale, du corps calleux et du thalamus a été observée chez un patient (12,5 %) chacun. Une restriction de diffusion a été observée chez 6 enfants, tous présentaient un sensorium altéré. L'IRM conventionnelle est un excellent outil pour le diagnostic du LS chez les enfants présentant des soupçon. L'encéphalopathie aiguë se présente fréquemment avec une restriction de diffusion correspondant à des lésions actives. Par conséquent, la restriction de diffusion sur L'IRM prédit l'activité des lésions chez les patients atteints du LS. Mots-clés : ganglions de la base, tronc cérébral, imagerie pondérée en diffusion, hypotonie, lactate sérique.
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Encefalopatías , Enfermedad de Leigh , Niño , Humanos , Preescolar , Lactante , Enfermedad de Leigh/diagnóstico por imagen , Estudios Retrospectivos , Imagen por Resonancia Magnética , Espectroscopía de Resonancia MagnéticaRESUMEN
Pyridine Nucleotide-Disulfide Oxidoreductase Domain 2 (PYROXD2; previously called YueF) is a mitochondrial inner membrane/matrix-residing protein and is reported to regulate mitochondrial function. The clinical importance of PYROXD2 has been unclear, and little is known of the protein's precise biological function. In the present paper, we report biallelic variants in PYROXD2 identified by genome sequencing in a patient with suspected mitochondrial disease. The child presented with acute neurological deterioration, unresponsive episodes, and extreme metabolic acidosis, and received rapid genomic testing. He died shortly after. Magnetic resonance imaging (MRI) brain imaging showed changes resembling Leigh syndrome, one of the more common childhood mitochondrial neurological diseases. Functional studies in patient fibroblasts showed a heightened sensitivity to mitochondrial metabolic stress and increased mitochondrial superoxide levels. Quantitative proteomic analysis demonstrated decreased levels of subunits of the mitochondrial respiratory chain complex I, and both the small and large subunits of the mitochondrial ribosome, suggesting a mitoribosomal defect. Our findings support the critical role of PYROXD2 in human cells, and suggest that the biallelic PYROXD2 variants are associated with mitochondrial dysfunction, and can plausibly explain the child's clinical presentation.
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Enfermedad de Leigh/diagnóstico por imagen , Mutación Missense , Proteínas Supresoras de Tumor/genética , Resultado Fatal , Humanos , Lactante , Enfermedad de Leigh/genética , Imagen por Resonancia Magnética , Masculino , Proteínas Mitocondriales/metabolismo , Modelos Moleculares , Proteómica , Análisis de Secuencia de ARN , Proteínas Supresoras de Tumor/química , Secuenciación Completa del GenomaRESUMEN
Variants in SURF1, encoding an assembly factor of mitochondrial respiratory chain complex IV, cause Leigh syndrome (LS) and Charcot-Marie-Tooth type 4K in children and young adolescents. Magnetic resonance imaging (MRI) appearance of enlarged nerve roots with postcontrastographic enhancement is a distinctive feature of hypertrophic neuropathy caused by onion-bulb formation and it has rarely been described in mitochondrial diseases (MDs). Spinal nerve roots abnormalities on MRI are novel findings in LS associated with variants in SURF1. Here we report detailed neuroradiological and neurophysiologic findings in a child with LS and demyelinating neuropathy SURF1-related. Our case underlines the potential contributive role of spinal neuroimaging together with neurophysiological examination to identify the full spectrum of patterns in MDs. It remains to elucidate if these observations remain peculiar of SURF1 variants or potentially detectable in other MDs with peripheral nervous system involvement.
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Enfermedad de Charcot-Marie-Tooth , Enfermedad de Leigh , Adolescente , Enfermedad de Charcot-Marie-Tooth/diagnóstico por imagen , Enfermedad de Charcot-Marie-Tooth/genética , Niño , Humanos , Enfermedad de Leigh/diagnóstico por imagen , Imagen por Resonancia Magnética , Proteínas de la Membrana/genética , Proteínas Mitocondriales/genética , Mutación , Raíces Nerviosas Espinales/diagnóstico por imagenRESUMEN
Leigh syndrome (LS) is a neurodegenerative disease characterized by bilaterally symmetric brainstem or basal ganglia lesions. More than 80 genes, largely impacting mitochondrial energy metabolism, can underlie LS, and no approved medicines exist. Described 70 years ago, LS was initially diagnosed by the characteristic, necrotic lesions on autopsy. It has been broadly assumed that antemortem neuroimaging abnormalities in these regions correspond to end-stage histopathology. However, clinical observations and animal studies suggest that neuroimaging findings may represent an intermediate state, that is more dynamic than previously appreciated, and even reversible. We review this literature, discuss related conditions that are treatable, and present two new LS cases with radiographic improvement. We review studies in which hypoxia reverses advanced LS in a mouse model. The fluctuating and potentially reversible nature of radiographic LS lesions will be important in clinical trial design. Better understanding of this plasticity could lead to new therapies.
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Enfermedad de Leigh , Enfermedades Neurodegenerativas , Animales , Modelos Animales de Enfermedad , Humanos , Enfermedad de Leigh/diagnóstico por imagen , Enfermedad de Leigh/genética , Ratones , Mutación , NeuroimagenRESUMEN
OBJECTIVES: Mitochondrial DNA (mtDNA)-associated Leigh syndrome (LS) is characterized by maternal inheritance, and the heteroplasmic mutant load of mtDNA pathogenic variants is known to affect clinical phenotypes. Among mtDNA pathogenic variants, variants of the MT-ATP6 gene account for most of reported cases. In this report, we aimed to describe the clinical and genetic findings of MT-ATP6-associated LS patients diagnosed at a single tertiary institution in Korea. METHODS: Thirteen patients with genetically confirmed MT-ATP6-associated LS were selected. We reviewed each patient's clinical findings, including general characteristics, biochemical parameters, brain MR images, muscle biopsy results, and heteroplasmic mutant load over a long-term follow-up period. RESULTS: MT-ATP6-associated LS was of predominantly early onset (age <2 years), although we identified 2 late-onset (>60 months) LS patients. The heteroplasmic mutant load estimated by next-generation sequencing was 96%-100% in all nucleotide change groups. Compared with other forms of MT-ATP6-associated LS, the m.8993T>G point mutation elicited a significantly higher rate of symptom onset before 2 years of age. Brain MRI showed bilateral basal ganglia involvement in all patients, followed by cerebral atrophy, brainstem and thalamus involvement, and cerebellar atrophy. After follow-up (median 7.2 years, range 1.4 to 11.5 years), LS with m.8993T>G point mutations had a slightly more severe clinical progression compared with other forms of MT-ATP6-associated LS. CONCLUSIONS: MT-ATP6-associated LS patients presented with a broad spectrum of clinical diagnoses and had a very high heteroplasmic mutant load. This study provides valuable data on MT-ATP6-associated LS that will inform subsequent studies on LS.
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Enfermedad de Leigh , Niño , Preescolar , ADN Mitocondrial/genética , Genotipo , Humanos , Enfermedad de Leigh/diagnóstico por imagen , Enfermedad de Leigh/genética , ATPasas de Translocación de Protón Mitocondriales/genética , Mutación/genética , FenotipoRESUMEN
ABSTRACT: Leigh syndrome is a rare progressive neurodegenerative disease with variable clinical presentations associated with mitochondrial dysfunction. However, the most common presentations are motor and intellectual developmental delays, with signs and symptoms of brainstem and basal ganglia involvement. We describe a 6-year-old boy with a history of delayed developmental milestones who presen-ted to our hospital due to unconscious status and respiratory distress syndrome. The patient underwent brain magnetic resonance imaging (MRI), and multiple subacute necrotic lesions were identified at the bilateral basal ganglia, thalamus, cerebral peduncles, brainstem, and cortical regions. DNA analysis was performed, which revealed muta-tions in SURF1. The patient experienced several relapses and died of respiratory failure and hospital-acquired infections, 3 years after the diagnosis of Leigh syndrome. Leigh syndrome should be considered in children with neurological problems and bilateral basal ganglia or brainstem abnormalities. Neurological MRI can be useful for guiding clinicians in ordering the most appropriate enzymatic and genetic analyses for further diagnosis.
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Enfermedad de Leigh , Enfermedades Neurodegenerativas , Encéfalo , Niño , Humanos , Enfermedad de Leigh/diagnóstico por imagen , Enfermedad de Leigh/genética , Imagen por Resonancia Magnética , Masculino , MutaciónRESUMEN
Mitochondrial disorders have been an enigma for a long time due to the varied clinical presentations. Although a genetic confirmation will be mandatory most of the time, half the number of Leigh syndrome would be negative for genetic mutations. There are a growing number of mutations in clinical practice, which escape detection on routine clinical exome sequencing. Imaging would render help in pointing towards a mitochondrial disorder. There are a few case reports which brief about specific mitochondrial mutations and their specific imaging appearance. This article tries to provide a comprehensive review on the imaging-genomic correlation of mitochondrial disorders with an objective of performing a specific genetic testing to arrive at an accurate diagnosis.
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Enfermedad de Leigh , Enfermedades Mitocondriales , Genómica , Humanos , Enfermedad de Leigh/diagnóstico por imagen , Enfermedad de Leigh/genética , Enfermedades Mitocondriales/diagnóstico por imagen , Enfermedades Mitocondriales/genética , MutaciónRESUMEN
Leigh syndrome is a progressive neurodegenerative syndrome caused by multiple mitochondrial DNA and nuclear DNA pathological variants. Patients with Leigh syndrome consistently have distinct brain lesions found on MRI scanning involving abnormal signal in the basal ganglia, brainstem and/or cerebellum. Other clinical findings vary depending on the genetic etiology and epigenetic factors. Mitochondrial DNA-derived Leigh syndrome phenotype is thought to be modulated by heteroplasmy level. The classic example is the clinical expression of the pathological variant, m. 8993 T>G. At heteroplasmy levels above 90%, the resulting phenotype is Leigh syndrome, but at levels 70-90% patients present with a syndrome of neuropathy, ataxia and retinitis pigmentosa. We describe a 15-year old girl with homoplasmic variant in m.8993 T>G and clinical and biochemical findings consistent with Leigh syndrome but with normal brain MRI findings and without retinal abnormalities or ataxia.
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Heteroplasmia , Enfermedad de Leigh/genética , Polimorfismo de Nucleótido Simple , Adolescente , Ataxia/genética , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Femenino , Humanos , Enfermedad de Leigh/diagnóstico por imagen , Enfermedad de Leigh/patología , Imagen por Resonancia Magnética , Fenotipo , Retina/anomalíasRESUMEN
AIM: To investigate cerebral blood flow (CBF) in acute episodes of Leigh syndrome compared with basal state in patients carrying pathogenic mitochondrial disease gene variants responsible for neurometabolic disorders. METHOD: Arterial spin labelling (ASL) magnetic resonance imaging (MRI) sequences were used to measure CBF in 27 patients with mitochondrial respiratory chain enzyme deficiencies, ascribed to pathogenic variants of reported disease genes who were undergoing either urgent neuroimaging for acute episodes of Leigh syndrome (Group I: 15 MRI, seven females, eight males; mean age 7y; range 7mo-14y) or routine brain MRI (Group II: 15 MRI, eight females, seven males; mean age 5y 2mo; range 2mo-12y). RESULTS: Patients displayed markedly increased CBF in the striatum (2.8-fold greater, p<0.001 [1.05-2.53]) during acute episodes of Leigh syndrome compared to basal conditions. Detection of elevated CBF preceded identification of structural MRI lesions in four out of 15 cases. INTERPRETATION: Our results suggest that increased CBF is an overt hallmark of Leigh syndrome episodes and ASL MRI sequences should facilitate early diagnosis of acute episodes of Leigh syndrome, especially during the first attack in young children, when structural MRI is insufficiently informative.