RESUMEN
Hyperkinesias in a patient with complex-I deficiency due to the variant m.10191T>C in MT-ND3 have not been previously reported. The patient is a 32 years-old female with multisystem mitochondrial disease due to variant m.10191T>C in MT-ND3, who has been experiencing episodic, spontaneous or induced abnormal movements since age 23. The abnormal movements started as right hemi-athetosis, bilateral dystonia of the legs, or unilateral dystonia of the right arm and leg. They often progressed to severe ballism, involving the trunk, and limbs. The arms were more dystonic than the legs. In conclusion, complex-I deficiency due to the variant m.10191T>C in MT-ND3 may manifest as multisystem disease including hyperkinesias. Neurologists should be aware of hyperkinesias as a manifestation of complex-I deficiency.
RésuméL'hyperkinésie d'une patiente atteinte d'un déficit en complexe I dû à la variante m.10191T>C du gène MT-ND3 n'a jamais été rapportée auparavant. La patiente est une femme de 32 ans atteinte d'une maladie mitochondriale multisystémique due à la variante m.10191T>C du gène MT-ND3, qui présente des mouvements anormaux épisodiques, spontanés ou provoqués depuis l'âge de 18 ans. mouvements anormaux épisodiques, spontanés ou provoqués depuis l'âge de 23 ans. Les mouvements anormaux ont commencé par une hémiathétose droite, dystonie bilatérale des jambes ou dystonie unilatérale du bras et de la jambe droite. Ils ont souvent évolué vers un ballisme sévère, impliquant le tronc et les membres. le tronc et les membres. Les bras étaient plus dystoniques que les jambes. En conclusion, le déficit en complexe I dû à la variante m.10191T>C du gène MT-ND3 peut se manifester par une maladie multisystémique comprenant des hyperkinésies. Les neurologues doivent être conscients que l'hyperkinésie est une manifestation du déficit en complexe-I. de la déficience en complexe I.
Asunto(s)
Enfermedad de Leigh , Humanos , Femenino , Adulto , Enfermedad de Leigh/complicaciones , Enfermedad de Leigh/diagnóstico , Hipercinesia/etiología , Complejo I de Transporte de Electrón/deficiencia , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , MutaciónRESUMEN
BACKGROUND: Six percent of patients with Leigh syndrome (LS) present with infantile epileptic spasms syndrome (IESS). However, treatment strategies for IESS with LS remain unclear. This retrospective study aimed to evaluate the efficacy and safety of treatment strategies in patients with IESS complicated by LS and Leigh-like syndrome (LLS). METHODS: We distributed questionnaires to 750 facilities in Japan, and the clinical data of 21 patients from 15 hospitals were collected. The data comprised treatment strategies, including adrenocorticotropic hormone (ACTH) therapy, ketogenic diet (KD) therapy, and antiseizure medications (ASMs); effectiveness of each treatment; and the adverse events. RESULTS: The median age at LS and LLS diagnosis was 7 months (range: 0 to 50), whereas that at the onset of epileptic spasms was 7 (range: 3 to 20). LS was diagnosed in 17 patients and LLS in four patients. Seven, two, five, and seven patients received ACTH + ASMs, ACTH + KD + ASMs, KD + ASMs, and ASMs only, respectively. Four (44%) of nine patients treated with ACTH and one (14%) of seven patients treated with KD achieved electroclinical remission within one month of treatment. No patients treated with only ASMs achieved electroclinical remission. Seven patients (33%) achieved electroclinical remission by the last follow-up. Adverse events were reported in four patients treated with ACTH, none treated with KD therapy, and eight treated with ASMs. CONCLUSION: ACTH therapy shows the best efficacy and rapid action in patients with IESS complicated by LS and LLS. The effectiveness of KD therapy and ASMs in this study was insufficient.
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Hormona Adrenocorticotrópica , Anticonvulsivantes , Dieta Cetogénica , Enfermedad de Leigh , Espasmos Infantiles , Humanos , Enfermedad de Leigh/complicaciones , Lactante , Espasmos Infantiles/tratamiento farmacológico , Espasmos Infantiles/complicaciones , Estudios Retrospectivos , Femenino , Masculino , Anticonvulsivantes/uso terapéutico , Japón , Preescolar , Hormona Adrenocorticotrópica/administración & dosificación , Recién NacidoRESUMEN
PURPOSE: RNF213, encoding a giant E3 ubiquitin ligase, has been recognized for its role as a key susceptibility gene for moyamoya disease. Case reports have also implicated specific variants in RNF213 with an early-onset form of moyamoya disease with full penetrance. We aimed to expand the phenotypic spectrum of monogenic RNF213-related disease and to evaluate genotype-phenotype correlations. METHODS: Patients were identified through reanalysis of exome sequencing data of an unselected cohort of unsolved pediatric cases and through GeneMatcher or ClinVar. Functional characterization was done by proteomics analysis and oxidative phosphorylation enzyme activities using patient-derived fibroblasts. RESULTS: We identified 14 individuals from 13 unrelated families with (de novo) missense variants in RNF213 clustering within or around the Really Interesting New Gene (RING) domain. Individuals presented either with early-onset stroke (n = 11) or with Leigh syndrome (n = 3). No genotype-phenotype correlation could be established. Proteomics using patient-derived fibroblasts revealed no significant differences between clinical subgroups. 3D modeling revealed a clustering of missense variants in the tertiary structure of RNF213 potentially affecting zinc-binding suggesting a gain-of-function or dominant negative effect. CONCLUSION: De novo missense variants in RNF213 clustering in the E3 RING or other regions affecting zinc-binding lead to an early-onset syndrome characterized by stroke or Leigh syndrome.
Asunto(s)
Enfermedad de Leigh , Enfermedad de Moyamoya , Accidente Cerebrovascular , Humanos , Niño , Enfermedad de Moyamoya/genética , Enfermedad de Leigh/complicaciones , Factores de Transcripción/genética , Ubiquitina-Proteína Ligasas/genética , Zinc , Predisposición Genética a la Enfermedad , Adenosina Trifosfatasas/genéticaRESUMEN
BACKGROUND: Rare mutations in NADH:ubiquinone oxidoreductase complex assembly factor 5 (NDUFAF5) are linked to Leigh syndrome. OBJECTIVE: We aimed to describe clinical characteristics and functional findings in a patient cohort with NDUFAF5 mutations. METHODS: Patients with biallelic NDUFAF5 mutations were recruited from multi-centers in Taiwan. Clinical, laboratory, radiological, and follow-up features were recorded and mitochondrial assays were performed in patients' skin fibroblasts. RESULTS: Nine patients from seven unrelated pedigrees were enrolled, eight homozygous for c.836 T > G (p.Met279Arg) in NDUFAF5 and one compound heterozygous for p.Met279Arg. Onset age had a bimodal distribution. The early-onset group (age <3 years) presented with psychomotor delay, seizure, respiratory failure, and hyponatremia. The late-onset group (age ≥5 years) presented with normal development, but slowly progressive dystonia. Combing 25 previously described patients, the p.Met279Arg variant was exclusively identified in Chinese ancestry. Compared with other groups, patients with late-onset homozygous p.Met279Arg were older at onset (P = 0.008), had less developmental delay (P = 0.01), less hyponatremia (P = 0.01), and better prognosis with preserved ambulatory function into early adulthood (P = 0.01). Bilateral basal ganglia necrosis was a common radiological feature, but brainstem and spinal cord involvement was more common with early-onset patients (P = 0.02). A modifier gene analysis showed higher concomitant mutation burden in early-versus late-onset p.Met279Arg homozygous cases (P = 0.04), consistent with more impaired mitochondrial function in fibroblasts from an early-onset case than a late-onset patient. CONCLUSIONS: The p.Met279Arg variant is a common mutation in our population with phenotypic heterogeneity and divergent prognosis based on age at onset. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Trastornos Distónicos , Hiponatremia , Enfermedad de Leigh , Trastornos del Movimiento , Preescolar , Humanos , Trastornos Distónicos/complicaciones , Hiponatremia/complicaciones , Enfermedad de Leigh/genética , Enfermedad de Leigh/complicaciones , Metiltransferasas/genética , Proteínas Mitocondriales/genética , Trastornos del Movimiento/complicaciones , Mutación/genética , Niño , Adulto JovenRESUMEN
Mitochondrial disorders can present with a wide range of clinical and biochemical phenotypes. Mitochondrial DNA variants may be influenced by factors such as degree of heteroplasmy and tissue distribution. We present a four-generation family in which 10 individuals carry a pathogenic mitochondrial variant (m.5537_5538insT, MT-TW gene) with differing levels of heteroplasmy and clinical features. This genetic variant has been documented in two prior reports, both in individuals with Leigh syndrome. In the current family, three individuals have severe mitochondrial symptoms including Leigh syndrome (patient 1, 100% in blood), MELAS (patient 2, 97% heteroplasmy in muscle), and MELAS-like syndrome (patient 3, 50% heteroplasmy in blood and 100% in urine). Two individuals have mild mitochondrial symptoms (patient 4, 50% in blood and 67% in urine and patient 5, 50% heteroplasmy in blood and 30% in urine). We observe that this variant is associated with multiple mitochondrial presentations and phenotypes, including MELAS syndrome for which this variant has not previously been reported. We also demonstrate that the level of heteroplasmy of the mitochondrial DNA variant correlates with the severity of clinical presentation; however, not with the specific mitochondrial syndrome.
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Enfermedad de Leigh , Síndrome MELAS , Enfermedades Mitocondriales , Humanos , Síndrome MELAS/diagnóstico , Síndrome MELAS/genética , Síndrome MELAS/complicaciones , Enfermedad de Leigh/diagnóstico , Enfermedad de Leigh/genética , Enfermedad de Leigh/complicaciones , Mitocondrias/genética , ADN Mitocondrial/genética , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/complicacionesRESUMEN
BACKGROUND: Leigh syndrome (LS) is a progressive neurodegenerative mitochondrial disease characterized by necrotizing lesions affecting different parts of the central nervous system, especially in the brainstem and basal ganglia. Lesions in this area may involve respiratory and sleep centers, resulting in the clinically significant disturbances seen-but poorly characterized-in LS. The purpose of the present study is to characterize and compare the physiologic responses to respiratory disturbances quantified by polysomnography metrics of children with LS with age-sex- and apnea-hypopnea index (AHI)-matched patients with obstructive sleep apnea (OSA), a common clinical population with similar burden of sleep-disordered breathing. METHODS: Retrospective comparative study of polysomnographic data from six patients with LS were reviewed and compared with 18 age-sex-AHI-matched patients with OSA, with particular attention to cardiorespiratory and sleep architecture metrics. RESULTS: Sleep architecture and stage duration were conserved in LS and OSA groups, but increased wake after sleep onset was seen among the first group. The LS group exhibited both obstructive and central sleep apnea. The group also had significantly greater values of heart rate, ≥3% oxygen desaturation index, and lower values of sleep efficiency, respiratory arousal index, and total sleep time when compared with the OSA group. CONCLUSIONS: Patients with LS exhibited significantly more sleep-related cardiorespiratory disturbances and sleep fragmentation when compared with neurotypical children with OSA. Given that these findings are plausibly detrimental to health and development, sleep evaluation in patients with similar conditions should be encouraged for early management.
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Enfermedad de Leigh , Apnea Obstructiva del Sueño , Niño , Humanos , Enfermedad de Leigh/complicaciones , Oxígeno , Estudios Retrospectivos , Sueño , Apnea Obstructiva del Sueño/complicacionesRESUMEN
BACKGROUND: Leigh syndrome (LS) is a rare, progressive, and fatal neurodegenerative disease that occurs mainly in infants and children. Neonatal LS has not yet been fully described. METHODS: The study design was approved by the ethics review board of Shenzhen Children's Hospital. RESULTS: A 24-day-old full-term male infant presented with a 2-day history of lip cyanosis when crying in September 2021. He was born to nonconsanguineous Asian parents. After birth, the patient was fed poorly. A recurrent decrease in peripheral oxygen saturation and difficulty in weaning from mechanical ventilation during hospitalization were observed. There were no abnormalities on brain magnetic resonance imaging (MRI) or blood and urine organic acid analyses on admission. His lactic acid level increased markedly, and repeat MRI showed symmetrical abnormal signal areas in the bilateral basal ganglia and brainstem with disease progression. Trio whole-exome sequencing revealed 2 heterozygous mutations (c.64Câ >â T [p.R22X] and c.584Tâ >â C [p.L195S]) in NDUFS1. Based on these findings, mitochondrial respiratory chain complex I deficiency-related LS was diagnosed. The patient underwent tracheal intubation and mechanical ventilation for respiratory failure. His oxygen saturation levels were maintained at normal levels with partially assisted ventilation. He was administered broad-spectrum antibiotics, oral coenzyme Q10, multivitamins, and idebenone. During hospitalization, the patient developed progressive consciousness impairment and respiratory and circulatory failure. He died on day 30. CONCLUSION: Lip cyanosis is an important initial symptom in LS. Mild upper respiratory tract infections can induce LS and aggravate the disease. No abnormal changes in the brain MRI were observed in the early LS stages in this patient. Multiple MRIs and blood lactic acid tests during disease progression and genetic testing are important for prompt and accurate diagnosis of LS.
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Enfermedad de Leigh , Enfermedades Neurodegenerativas , Niño , Cianosis/genética , Progresión de la Enfermedad , Complejo I de Transporte de Electrón/deficiencia , Humanos , Lactante , Recién Nacido , Ácido Láctico , Enfermedad de Leigh/complicaciones , Enfermedad de Leigh/diagnóstico , Enfermedad de Leigh/genética , Labio , Masculino , Enfermedades Mitocondriales , Mutación , NADH DeshidrogenasaRESUMEN
BACKGROUND: POLG pathogenic variants are the commonest single-gene cause of inherited mitochondrial disease. However, the data on clinicogenetic associations in POLG-related disorders are sparse. This study maps the clinicogenetic spectrum of POLG-related disorders in the pediatric population. METHODS: Individuals were recruited across 6 centers in India. Children diagnosed between January 2015 and August 2020 with pathogenic or likely pathogenic POLG variants and age of onset <15 years were eligible. Phenotypically, patients were categorized into Alpers-Huttenlocher syndrome; myocerebrohepatopathy syndrome; myoclonic epilepsy, myopathy, and sensory ataxia; ataxia-neuropathy spectrum; Leigh disease; and autosomal dominant / recessive progressive external ophthalmoplegia. RESULTS: A total of 3729 genetic reports and 4256 hospital records were screened. Twenty-two patients with pathogenic variants were included. Phenotypically, patients were classifiable into Alpers-Huttenlocher syndrome (8/22; 36.4%), progressive external ophthalmoplegia (8/22; 36.4%), Leigh disease (2/22; 9.1%), ataxia-neuropathy spectrum (2/22; 9.1%), and unclassified (2/22; 9.1%). The prominent clinical manifestations included developmental delay (n = 14; 63.7%), neuroregression (n = 14; 63.7%), encephalopathy (n = 11; 50%), epilepsy (n = 11; 50%), ophthalmoplegia (n = 8; 36.4%), and liver dysfunction (n = 8; 36.4%). Forty-four pathogenic variants were identified at 13 loci, and these were clustered at exonuclease (18/44; 40.9%), linker (13/44; 29.5%), polymerase (10/44; 22.7%), and N-terminal domains (3/44; 6.8%). Genotype-phenotype analysis suggested that serious outcomes including neuroregression (odds ratio [OR] 11, 95% CI 2.5, 41), epilepsy (OR 9, 95% CI 2.4, 39), encephalopathy (OR 5.7, 95% CI 1.4, 19), and hepatic dysfunction (OR 4.6, 95% CI 21.3, 15) were associated with at least 1 variant involving linker or polymerase domain. CONCLUSIONS: We describe the clinical subgroups and their associations with different POLG domains. These can aid in the development of follow-up and management strategies of presymptomatic individuals.
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Esclerosis Cerebral Difusa de Schilder , Enfermedad de Leigh , Hepatopatías , Oftalmoplejía Externa Progresiva Crónica , Ataxia/genética , Niño , ADN Polimerasa gamma/genética , ADN Mitocondrial/genética , ADN Polimerasa Dirigida por ADN/genética , Esclerosis Cerebral Difusa de Schilder/complicaciones , Esclerosis Cerebral Difusa de Schilder/genética , Humanos , Enfermedad de Leigh/complicaciones , Hepatopatías/complicaciones , Enfermedades Mitocondriales , Mutación/genética , Oftalmoplejía Externa Progresiva Crónica/complicaciones , Oftalmoplejía Externa Progresiva Crónica/genéticaRESUMEN
Isolated biochemical deficiency of mitochondrial complex I is the most frequent signature among mitochondrial diseases and is associated with a wide variety of clinical symptoms. Leigh syndrome represents the most frequent neuroradiological finding in patients with complex I defect and more than 80 monogenic causes have been involved in the disease. In this report, we describe seven patients from four unrelated families harboring novel NDUFA12 variants, with six of them presenting with Leigh syndrome. Molecular genetic characterization was performed using next-generation sequencing combined with the Sanger method. Biochemical and protein studies were achieved by enzymatic activities, blue native gel electrophoresis, and western blot analysis. All patients displayed novel homozygous mutations in the NDUFA12 gene, leading to the virtual absence of the corresponding protein. Surprisingly, despite the fact that in none of the analyzed patients, NDUFA12 protein was detected, they present a different onset and clinical course of the disease. Our report expands the array of genetic alterations in NDUFA12 and underlines phenotype variability associated with NDUFA12 defect.
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Enfermedad de Leigh/genética , Enfermedades Mitocondriales/genética , NADPH Deshidrogenasa/genética , Adolescente , Niño , Preescolar , Estudios de Cohortes , Consanguinidad , Complejo I de Transporte de Electrón/genética , Familia , Femenino , Predisposición Genética a la Enfermedad , Humanos , Italia , Enfermedad de Leigh/complicaciones , Enfermedad de Leigh/patología , Masculino , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/patología , Fenotipo , Polimorfismo de Nucleótido SimpleRESUMEN
In clinical practice, intrathecal baclofen (ITB) therapy is used to control spasticity. After initial placement of the ITB pump, clinicians incrementally increase the dose until effectiveness in alleviating spasms and spasticity is optimized. However, this case describes a 4-year-old male with Leigh syndrome who developed a paradoxical worsening of spasticity and pain with incremental increase of his ITB pump. In this rare genetic disease with a poor prognosis, an ITB pump was trialed and implanted and titrated upwards with initial improvement. However, his spasticity and pain then began to worsen with each dosage increase. Subsequently, his symptoms improved significantly when the dose was weaned. This is the first case that describes this paradoxical reaction in a pediatric population and discusses recommendations about how clinicians should safely titrate the pump for patient care.
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Enfermedad de Leigh , Relajantes Musculares Centrales , Baclofeno , Niño , Preescolar , Humanos , Bombas de Infusión Implantables , Inyecciones Espinales , Enfermedad de Leigh/complicaciones , Enfermedad de Leigh/tratamiento farmacológico , Masculino , Espasticidad Muscular/tratamiento farmacológicoRESUMEN
The dysfunction of respiratory chain complex I (CI) is the most common form of mitochondrial disease that most often presents as Leigh syndrome (LS) in children - a severe neurometabolic disorder defined by progressive focal lesions in specific brain regions. The mechanisms underlying this region-specific vulnerability to CI deficiency, however, remain elusive. Here, we examined brain regional respiratory chain enzyme activities and metabolic profiles in a mouse model of LS with global CI deficiency to gain insight into regional vulnerability to neurodegeneration. One lesion-resistant and three lesion-prone brain regions were investigated in Ndufs4 knockout (KO) mice at the late stage of LS. Enzyme assays confirmed significantly decreased (60-80%) CI activity in all investigated KO brain regions, with the lesion-resistant region displaying the highest residual CI activity (38% of wild type). A higher residual CI activity, and a less perturbed NADH/NAD+ ratio, correlate with less severe metabolic perturbations in KO brain regions. Moreover, less perturbed BCAA oxidation and increased glutamate oxidation seem to distinguish lesion-resistant from -prone KO brain regions, thereby identifying key areas of metabolism to target in future therapeutic intervention studies.
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Aminoácidos de Cadena Ramificada/metabolismo , Modelos Animales de Enfermedad , Complejo I de Transporte de Electrón/metabolismo , Ácido Glutámico/metabolismo , Enfermedad de Leigh/complicaciones , Enfermedades Neurodegenerativas/patología , Animales , Complejo I de Transporte de Electrón/fisiología , Enfermedad de Leigh/metabolismo , Enfermedad de Leigh/patología , Masculino , Metaboloma , Ratones , Ratones Noqueados , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/metabolismo , Fosforilación OxidativaRESUMEN
BACKGROUND: Leigh syndrome (LS) is a mitochondrial disorder that shows abnormal basal ganglia lesion and psychomotor regression. Although vitamins have been used for LS, we have not found any effective drug. CASE PRESENTATION: A 26-year-old man who showed psychomotor delay and short stature at the age of 1 year was diagnosed with LS according to the results of cerebrospinal fluid and high signal intensity in the bilateral striatum on T2-weighted magnetic resonance imaging. He demonstrated psychomotor delay and breathing disorders, but the progression was very slow. His symptoms suddenly worsened at the age of 24 years after acute epididymitis. He showed epileptic seizures simultaneously and his activities of daily living (ADL) significantly worsened. Several antiepileptic drugs were ineffective, but his seizures were suppressed by a low dose of perampanel and his ADL improved. CONCLUSION AND DISCUSSION: Our case showed that low-dose perampanel could be a drug for epileptic seizures and improvement of ADL in patients with LS.
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Enfermedad de Leigh/complicaciones , Nitrilos/uso terapéutico , Piridonas/uso terapéutico , Convulsiones/tratamiento farmacológico , Actividades Cotidianas , Adulto , Anticonvulsivantes/uso terapéutico , Ganglios Basales , Epilepsia/tratamiento farmacológico , Humanos , Enfermedad de Leigh/tratamiento farmacológico , Imagen por Resonancia Magnética/métodos , Masculino , Mutación/genética , Resultado del TratamientoRESUMEN
We report clinicopathological findings of a patient with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes/Leigh syndrome (MELAS/LS) associated with a novel m.3482A>G mutation in MT-ND1. A 41-year-old woman had experienced multiple stroke-like episodes since age 16. She developed akinetic mutism two months before admission to our hospital. Neurological examination revealed akinetic mutism, bilateral deafness, and muscular atrophy. Cerebrospinal fluid tests revealed elevated pyruvate and lactate levels. Fluid-attenuated inversion recovery images on magnetic resonance imaging showed hyperintense areas in the right frontal and both sides of temporal and occipital lobes, both sides of the striatum, and the midbrain. Muscle biopsy revealed strongly succinate dehydrogenase-reactive blood vessels. L-arginine therapy improved her consciousness and prevented further stroke-like episodes. However, she died from aspiration pneumonia. Postmortem autopsy revealed scattered infarct-like lesions with cavitation in the cerebral cortex and necrotic lesions in the striatum and midbrain. The patient was pathologically confirmed as having MELAS/LS based on two characteristic clinicopathological findings: presenting MELAS/LS overlap phenotype and effectiveness of L-arginine treatment.
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Acidosis Láctica/patología , Enfermedad de Leigh/patología , Encefalomiopatías Mitocondriales/patología , Mutación , NADH Deshidrogenasa , Accidente Cerebrovascular/patología , Acidosis Láctica/complicaciones , Acidosis Láctica/genética , Adulto , Resultado Fatal , Femenino , Humanos , Enfermedad de Leigh/complicaciones , Enfermedad de Leigh/genética , Encefalomiopatías Mitocondriales/complicaciones , Encefalomiopatías Mitocondriales/genética , Mutación/genética , NADH Deshidrogenasa/genética , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/genéticaAsunto(s)
Edema Encefálico/diagnóstico por imagen , Edema Encefálico/genética , Cerebelo/diagnóstico por imagen , Enfermedad de Leigh/diagnóstico por imagen , Enfermedad de Leigh/genética , Atrofias Ópticas Hereditarias/diagnóstico por imagen , Atrofias Ópticas Hereditarias/genética , Edema Encefálico/etiología , Resultado Fatal , Femenino , Humanos , Enfermedad de Leigh/complicaciones , Atrofias Ópticas Hereditarias/complicaciones , Adulto JovenRESUMEN
SURF1 is a nuclear gene and encodes for an important assembly factor for cytochrome c oxidase enzyme. A number of mutations in SURF1 gene render cytochrome c oxidase deficiency, a major causative factor for Leigh syndrome. We screened all the 9 exons and exon-intron boundaries of SURF1 gene in 165 Indian Leigh syndrome patients who were thiamine responsive too. Consequently, we identified several novel and reported nucleotide variations in this gene. The nucleotide changes were analysed by using different in-silico tools for predicting their pathogenicity. Based upon the predictions, we further validated the analyzed functional significance of p.N249D and p.P298L mutations in SURF1 protein using COS-7 cells. Though, both the mutations did not affect the localization of SURF1protein into the mitochondria. But, interestingly the novel mutation p.P298L was reported to significantly compromise the COX activity in these cells.
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Enfermedad de Leigh/genética , Proteínas de la Membrana/genética , Proteínas Mitocondriales/genética , Polimorfismo de Nucleótido Simple , Deficiencia de Tiamina/genética , Animales , Células COS , Niño , Chlorocebus aethiops , Complejo IV de Transporte de Electrones/metabolismo , Predisposición Genética a la Enfermedad , Humanos , India , Enfermedad de Leigh/complicaciones , Enfermedad de Leigh/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Mitocondriales/metabolismo , Deficiencia de Tiamina/metabolismoRESUMEN
COX15 mutations were shown to underlie Leigh syndrome (LS), a progressive subacute necrotizing encephalopathy caused by defects in the mitochondrial respiratory chain. Here, two siblings of consanguineous kindred presented in infancy with a syndrome of hypotonia, nystagmus, psychomotor retardation, and pyramidal signs. Toward the end of their second year, both patients developed progressive quadriparesis, convulsions, and pseudobulbar palsy. Similar to two previously reported cases, one of the two affected siblings had severe hypertrophic obstructive cardiomyopathy, hearing loss, and no visual response. Through linkage analysis and whole-exome sequencing, we identified a homozygous p.R217W mutation in Cytochrome C oxidase assembly protein COX15 homolog. Consistent with the known heterogeneity of mitochondrial diseases in general and that of LS in particular, several phenotypic features were markedly distinguished between the affected siblings and in relation to previous reports of COX15 mutations. Interestingly, of the previously reported five cases of COX15-mutated patients, all of different ethnic origins, three had a p.R217W mutation. We highlight p.R217W as a hotspot mutation in COX15 and delineate the phenotypic variability, both between the patients we describe and in all cases reported to date.