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1.
Neurology ; 103(1): e209541, 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38857477

RESUMEN

BACKGROUND AND OBJECTIVES: Aicardi Goutières syndrome (AGS) is type I interferonopathy characterized by severe neurologic impairment. Although many children with AGS demonstrate motor and expressive language deficits, the magnitude of receptive language impairment is uncharacterized. We sought to characterize cognitive function in AGS-affected children using assessment tools with reduced dependence on motor abilities and compare cognitive testing outcomes with overall severity and parental assessment of adaptive behavior. METHODS: We performed a cross-sectional study. Children were recruited as part of the Myelin Disorders Biorepository Project at the Children's Hospital of Philadelphia. We included individuals with a confirmed diagnosis of AGS. We administered the Leiter International Performance Scale, third edition (Leiter-3), and the Vineland Adaptive Behavior Scale, third edition (VABS-3), in the context of research encounters. Motor skills were categorized by AGS Severity Scale mobility levels. Descriptive statistics and Spearman's rank correlation were used to compare assessments. Mann-Whitney and Kruskal-Wallis tests with correction with Dunn's multiple comparison test were used to compare test performance between mobility groups. RESULTS: Cognitive and adaptive behavior performance was captured in 57 children. The mean age at encounters was 8.51 (SD 5.15) years. The median (IQR) Leiter-3 score was 51 (interquartile range [IQR] 60), with administration failure in 20 of 57 (35%) individuals. On the VABS-3, the Motor Domain (median 29, IQR 36.25) was more impacted than the Communication (median 50, IQR 52), Daily Living Skills (median 52, IQR 31), and Socialization (median 54, IQR 40) Domains (p < 0.0001). The AGS Scale correlated with VABS-3 (r = 0.86, p < 0.0001) and Leiter-3 (r = 0.87, p < 0.0001). There was correlation between VABS-3 Domains and Leiter-3 (r-range 0.83-0.97). Gross motor and fine motor categories, respectively, correlated with VABS-3 (H = 39.37, p < 0.0001; U = 63, p < 0.0001) and Leiter-3 (H = 40.43, p < 0.0001; U = 66, p < 0.0001). Within each gross motor and fine motor category of the AGS Scale, a subset of children scored within normal IQ range. DISCUSSION: Parental assessment of function by the VABS-3 correlated with directly assessed performance measures. Our data underscore the potential value of VABS-3 and Leiter-3 as tools to assess psychometric function in AGS. With a deeper understanding of our patients' abilities, we can better guide clinicians and families to provide appropriate support and personalized interventions to empower children with leukodystrophies to maximize their communication and educational potential.


Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso , Malformaciones del Sistema Nervioso , Humanos , Femenino , Masculino , Estudios Transversales , Niño , Enfermedades Autoinmunes del Sistema Nervioso/fisiopatología , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico , Enfermedades Autoinmunes del Sistema Nervioso/complicaciones , Enfermedades Autoinmunes del Sistema Nervioso/psicología , Preescolar , Malformaciones del Sistema Nervioso/psicología , Malformaciones del Sistema Nervioso/complicaciones , Cognición/fisiología , Adolescente , Pruebas Neuropsicológicas , Adaptación Psicológica , Destreza Motora , Índice de Severidad de la Enfermedad
2.
Sci Immunol ; 9(95): eadk0865, 2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38701189

RESUMEN

Dysregulated B cell cytokine production contributes to pathogenesis of immune-mediated diseases including multiple sclerosis (MS); however, the underlying mechanisms are poorly understood. In this study we investigated how cytokine secretion by pro-inflammatory (GM-CSF-expressing) and anti-inflammatory (IL-10-expressing) B cells is regulated. Pro-inflammatory human B cells required increased oxidative phosphorylation (OXPHOS) compared with anti-inflammatory B cells. OXPHOS reciprocally modulated pro- and anti-inflammatory B cell cytokines through regulation of adenosine triphosphate (ATP) signaling. Partial inhibition of OXPHOS or ATP-signaling including with BTK inhibition resulted in an anti-inflammatory B cell cytokine shift, reversed the B cell cytokine imbalance in patients with MS, and ameliorated neuroinflammation in a myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalitis mouse model. Our study identifies how pro- and anti-inflammatory cytokines are metabolically regulated in B cells and identifies ATP and its metabolites as a "fourth signal" that shapes B cell responses and is a potential target for restoring the B cell cytokine balance in autoimmune diseases.


Asunto(s)
Linfocitos B , Citocinas , Encefalomielitis Autoinmune Experimental , Inflamación , Esclerosis Múltiple , Fosforilación Oxidativa , Animales , Esclerosis Múltiple/inmunología , Humanos , Citocinas/inmunología , Citocinas/metabolismo , Ratones , Linfocitos B/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Inflamación/inmunología , Femenino , Masculino , Ratones Endogámicos C57BL , Adulto , Adenosina Trifosfato/metabolismo , Persona de Mediana Edad
3.
J Child Neurol ; 39(3-4): 147-154, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38532733

RESUMEN

Aicardi-Goutières syndrome is a genetic inflammatory disorder resulting in dispersed neurologic dysfunction. Despite a recognition of overall motor impairment, fine and visual motor skills are undercharacterized. We hypothesize that there is a spectrum of fine and visual motor skills in the Aicardi-Goutières syndrome population as captured by a standard outcome measure, the Peabody Developmental Motor Scales (PDMS-2), which will be proportional to overall disease severity.In a cohort of 74 subjects, the Peabody Developmental Motor Scales-2 grasping and visual-motor integration subtests were administered concurrently with the Aicardi-Goutières syndrome Severity Scale (severe [range 0-3], moderate [range 4-8], and attenuated [range 9-11]). The cohort was also compared by genotype and performance as defined by raw scores. The distribution of Peabody Developmental Motor Scales-2 scores within a genotype was assessed by interquartile ranges (IQRs).Peabody Developmental Motor Scales-2 grasping and visual-motor integration performance was the least variable in the TREX1-cohort (IQR: 10.00-12.00) versus the SAMHD1 and IFIH1 cohorts (IQR: 51.00-132.00 and 48.50-134.00, respectively). Neurologic severity highly correlated with both fine and visual motor skills (Spearman correlation: r = 0.87, 0.91, respectively). A floor effect (lowest 10% of possible scores) was observed within the severe cohort (n = 32/35), whereas a ceiling effect (top 10%) was observed in the attenuated cohort (n = 13/17).This study characterized the spectrum of fine and visual motor function in the Aicardi-Goutières syndrome population, which correlated with overall neurologic dysfunction. The Peabody Developmental Motor Scales-2 grasping and visual-motor integration showed promise as potential assessment tools in moderate and attenuated Aicardi-Goutières syndrome cohorts. A better understanding of fine and visual motor function in this population will benefit clinical care and clinical trial design.


Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso , Destreza Motora , Malformaciones del Sistema Nervioso , Humanos , Femenino , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/fisiopatología , Malformaciones del Sistema Nervioso/complicaciones , Masculino , Niño , Enfermedades Autoinmunes del Sistema Nervioso/genética , Enfermedades Autoinmunes del Sistema Nervioso/fisiopatología , Enfermedades Autoinmunes del Sistema Nervioso/complicaciones , Destreza Motora/fisiología , Preescolar , Estudios de Cohortes , Índice de Severidad de la Enfermedad , Adolescente , Lactante , Desempeño Psicomotor/fisiología
4.
Mol Genet Metab ; 142(1): 108453, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38522179

RESUMEN

Growing interest in therapeutic development for rare diseases necessitate a systematic approach to the collection and curation of natural history data that can be applied consistently across this group of heterogenous rare diseases. In this study, we discuss the challenges facing natural history studies for leukodystrophies and detail a novel standardized approach to creating a longitudinal natural history study using existing medical records. Prospective studies are uniquely challenging for rare diseases. Delays in diagnosis and overall rarity limit the timely collection of natural history data. When feasible, prospective studies are often cross-sectional rather than longitudinal and are unlikely to capture pre- or early- symptomatic disease trajectories, limiting their utility in characterizing the full natural history of the disease. Therapeutic development in leukodystrophies is subject to these same obstacles. The Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) comprises of a network of research institutions across the United States, supported by a multi-center biorepository protocol, to map the longitudinal clinical course of disease across leukodystrophies. As part of GLIA-CTN, we developed Standard Operating Procedures (SOPs) that delineated all study processes related to staff training, source documentation, and data sharing. Additionally, the SOP detailed the standardized approach to data extraction including diagnosis, clinical presentation, and medical events, such as age at gastrostomy tube placement. The key variables for extraction were selected through face validity, and common electronic case report forms (eCRF) across leukodystrophies were created to collect analyzable data. To enhance the depth of the data, clinical notes are extracted into "original" and "imputed" encounters, with imputed encounter referring to a historic event (e.g., loss of ambulation 3 months prior). Retrospective Functional Assessments were assigned by child neurologists, using a blinded dual-rater approach and score discrepancies were adjudicated by a third rater. Upon completion of extraction, data source verification is performed. Data missingness was evaluated using statistics. The proposed methodology will enable us to leverage existing medical records to address the persistent gap in natural history data within this unique disease group, allow for assessment of clinical trajectory both pre- and post-formal diagnosis, and promote recruitment of larger cohorts.


Asunto(s)
Enfermedades Raras , Humanos , Enfermedades Raras/diagnóstico , Enfermedades Raras/terapia , Enfermedades Raras/epidemiología , Estudios Longitudinales , Estados Unidos , Estudios Prospectivos
5.
Mol Genet Metab ; 142(1): 108346, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38368708

RESUMEN

OBJECTIVE: Aicardi Goutières Syndrome (AGS) is a genetic interferonopathy associated with multisystemic heterogeneous disease and neurologic dysfunction. AGS includes a broad phenotypic spectrum which is only partially explained by genotype. To better characterize this variability, we will perform a systematic analysis of phenotypic variability in familial cases of AGS. METHODS: Among thirteen families, twenty-six siblings diagnosed with AGS were identified from the Myelin Disorders and Biorepository Project (MDBP) at the Children's Hospital of Philadelphia. Data were collected on the age of onset, genotype, neurologic impairment, and systemic complications. Neurologic impairment was assessed by a disease-specific scale (AGS Severity Scale) at the last available clinical encounter (range: 0-11 representing severe - attenuated phenotypes). The concordance of clinical severity within sibling pairs was categorized based on the difference in AGS Scale (discordant defined as >2-unit difference). The severity classifications were compared between sibling sets and by genotype. RESULTS: Five genotypes were represented: TREX1 (n = 4 subjects), RNASEH2B (n = 8), SAMHD1 (n = 8) ADAR1 (n = 4), and IFIH1 (n = 2). The older sibling was diagnosed later relative to the younger affected sibling (median age 7.32 years [IQR = 14.1] compared to 1.54 years [IQR = 10.3]). Common presenting neurologic symptoms were tone abnormalities (n = 10/26) and gross motor dysfunction (n = 9/26). Common early systemic complications included dysphagia and chilblains. The overall cohort median AGS severity score at the last encounter was 8, while subjects presenting with symptoms before one year had a median score of 5. The TREX1 cohort presented at the youngest age and with the most severe phenotype on average. AGS scores were discordant for 5 of 13 sibling pairs, most commonly in the SAMHD1 pairs. Microcephaly, feeding tube placement, seizures and earlier onset sibling were associated with lower AGS scores (respectively, Wilcoxon rank sum: p = 0.0001, p < 0.0001, p = 0.0426, and Wilcoxon signed rank: p = 0.0239). CONCLUSIONS: In this systematic analysis of phenotypic variability in familial cases, we found discordance between siblings affected by AGS. Our results underscore the heterogeneity of AGS and suggest factors beyond AGS genotype may affect phenotype. Understanding the critical variables associated with disease onset and severity can guide future therapeutic interventions and clinical monitoring. This report reinforces the need for further studies to uncover potential factors to better understand this phenotypic variability, and consequently identify potential targets for interventions in attempt to change the natural history of the disease.


Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso , Exodesoxirribonucleasas , Estudios de Asociación Genética , Genotipo , Malformaciones del Sistema Nervioso , Fenotipo , Hermanos , Humanos , Enfermedades Autoinmunes del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/complicaciones , Femenino , Masculino , Preescolar , Niño , Lactante , Exodesoxirribonucleasas/genética , Fosfoproteínas/genética , Ribonucleasa H/genética , Proteína 1 que Contiene Dominios SAM y HD/genética , Adolescente , Proteínas de Unión al GTP Monoméricas/genética , Helicasa Inducida por Interferón IFIH1/genética , Mutación , Proteínas de Unión al ARN/genética , Edad de Inicio , Índice de Severidad de la Enfermedad
6.
Brain Sci ; 13(8)2023 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-37626525

RESUMEN

OBJECTIVE: To report a series of atypical presentations of Aicardi-Goutières syndrome. METHODS: Clinical, neuroimaging, and genetic data. RESULTS: We report a series of six unrelated patients (five males) with a subacute loss of developmental milestones, pyramidal signs, and regression of communication abilities, with onset at ages ranging from 7 to 20 months, reaching a nadir after 4 to 24 weeks. A remarkable improvement of lost abilities occurred in the follow-up, and they remained with residual spasticity and dysarthria but preserved cognitive function. Immunization or febrile illness occurred before disease onset in all patients. CSF was normal in two patients, and in four, borderline or mild lymphocytosis was present. A brain CT scan disclosed a subtle basal ganglia calcification in one of six patients. Brain MRI showed asymmetric signal abnormalities of white matter with centrum semi-ovale involvement in five patients and a diffuse white matter abnormality with contrast enhancement in one. Four patients were diagnosed and treated for acute demyelinating encephalomyelitis (ADEM). Brain imaging was markedly improved with one year or more of follow-up (average of 7 years), but patients remained with residual spasticity and dysarthria without cognitive impairment. Demyelination relapse occurred in a single patient four years after the first event. Whole-exome sequencing (WES) was performed in all patients: four of them disclosed biallelic pathogenic variants in RNASEH2B (three homozygous p.Ala177Thr and one compound heterozygous p.Ala177Thr/p.Gln58*) and in two of them the same homozygous deleterious variants in RNASEH2A (p.Ala249Val). CONCLUSIONS: This report expands the phenotype of AGS to include subacute developmental regression with partial clinical and neuroimaging improvement. Those clinical features might be misdiagnosed as ADEM.

7.
Brain Sci ; 13(8)2023 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-37626566

RESUMEN

We report a 20-year-old, female, adopted Indian patient with over 662 Mb regions of homozy-gosity who presented with intellectual disability, ataxia, schizophrenia, retinal dystrophy, moder-ate-to-severe progressive sensorineural hearing loss (SNHL), congenital hypothyroidism, cleft mi-tral valve with mild mitral valve regurgitation, and dysmorphic features. Exome analysis first on a clinical basis and subsequently on research reanalysis uncovered pathogenic variants in three nu-clear genes following two modes of inheritance that were causal to her complex phenotype. These included (1) compound heterozygous variants in BBS6 potentially causative for Bardet-Biedl syn-drome 6; (2) a homozygous, known pathogenic variant in the stereocilin (STRC) gene associated with nonsyndromic deafness; and (3) a homozygous variant in dual oxidase 2 (DUOX2) gene asso-ciated with congenital hypothyroidism. A variant of uncertain significance was identified in a fourth gene, troponin T2 (TNNT2), associated with cardiomyopathy but not the cleft mitral valve, with mild mitral regurgitation seen in this case. This patient was the product of an apparent first-degree relationship, explaining the multiple independent inherited findings. This case high-lights the need to carefully evaluate multiple independent genetic etiologies for complex pheno-types, particularly in the case of consanguinity, rather than presuming unexplained features are expansions of known gene disorders.

8.
J Child Neurol ; 38(8-9): 518-527, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37499181

RESUMEN

Background: Aicardi-Goutières syndrome (AGS) is a rare genetic disorder characterized by a spectrum of motor abilities. While the Aicardi-Goutières syndrome severity score favors severely impacted individuals, there is an unmet need to define tools measuring function across the Aicardi-Goutières syndrome spectrum as potential outcome assessments for future clinical trials. Methods: Gross Motor Function Measure-88 (GMFM-88) and AGS Severity Scale were administered in individuals affected by Aicardi-Goutières syndrome (n = 71). We characterized the performance variability by genotype. Derived versions of the GMFM-88, including the GMFM-66, GMFM-66 item set (GMFM-66IS), and GMFM-66 Basal&Ceiling (GMFM-66BC) were calculated. The Aicardi-Goutières syndrome cohort was divided into severe (AGS Severity Scale score <4) or attenuated (≥4). Performance on the AGS Severity Scale highly correlated with total GMFM-88 scores (Spearman Correlation: R = 0.91). To assess variability of the GMFM-88 within genotypic subcohorts, interquartile ranges (IQRs) were compared. Results: GMFM-88 performance in the TREX1 cohort had least variability while the SAMHD1 cohort had the largest IQR (4.23 vs 81.8). Floor effect was prominent, with most evaluations scoring below 20% (n = 46, 64.79%), particularly in TREX1- and RNASEH2-cohorts. Performance by the GMFM-66, GMFM-66IS, and GMFM-66BC highly correlated with the full GMFM-88. The Aicardi-Goutières syndrome population represents a broad range of gross motor skills. Conclusions: This work identified the GMFM-88 as a potential clinical outcome assessment in subsets of the Aicardi-Goutières syndrome population but underscores the need for additional validation of outcome measures reflective of the diverse gross motor function observed in this population, including low motor function. When time is limited by resources or patient endurance, shorter versions of the GMFM-88 may be a reasonable alternative.


Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso , Malformaciones del Sistema Nervioso , Humanos , Malformaciones del Sistema Nervioso/genética , Enfermedades Autoinmunes del Sistema Nervioso/genética , Genotipo , Mutación
9.
Sci Adv ; 9(10): eade1463, 2023 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-36897941

RESUMEN

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.


Asunto(s)
Megalencefalia , Trastornos del Neurodesarrollo , Animales , Humanos , Ratones , Haploinsuficiencia , Metiltransferasas/genética , Ratones Noqueados , Trastornos del Neurodesarrollo/genética , Fenotipo
11.
Neurology ; 101(1): 46-49, 2023 07 04.
Artículo en Inglés | MEDLINE | ID: mdl-36805432

RESUMEN

Paroxysmal exercise-induced movement disorders may be caused by energy metabolism disorders, such as Glut 1 deficiency, pyruvate dehydrogenase deficiency, or mitochondrial respiratory chain disorders. A 4-year-old boy with a history of febrile seizures presented with paroxysmal dystonia, triggered by exercise, or occurring at rest. Additional investigations demonstrated pallidal hyperintensities on brain MRI and low CSF glucose. Pyruvate and lactate were elevated. The clinical presentation combined with neuroimaging abnormalities and biochemical profile (the lactate/pyruvate ratio) were clues to pyruvate dehydrogenase deficiency, a treatable metabolic disorder with neurologic presentations.


Asunto(s)
Corea , Distonía , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa , Masculino , Humanos , Preescolar , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/complicaciones , Distonía/etiología , Corea/complicaciones , Ácido Láctico , Ácido Pirúvico
12.
Neurohospitalist ; 13(1): 74-77, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36531844

RESUMEN

A 47-year-old man presented to his local hospital in Peru after a generalized tonic-clonic seizure. His family reported a history of prior stroke of unclear etiology. This case report discusses the approach to a first seizure (including in tropical regions like Peru), the relationship between stroke and seizures, the approach to stroke in the young, and how to diagnose rare diseases in resource-limited settings.

13.
Acta Neuropathol ; 143(4): 505-521, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35303161

RESUMEN

Inhibition of Bruton's Tyrosine Kinase (BTKi) is now viewed as a promising next-generation B-cell-targeting therapy for autoimmune diseases including multiple sclerosis (MS). Surprisingly little is known; however, about how BTKi influences MS disease-implicated functions of B cells. Here, we demonstrate that in addition to its expected impact on B-cell activation, BTKi attenuates B-cell:T-cell interactions via a novel mechanism involving modulation of B-cell metabolic pathways which, in turn, mediates an anti-inflammatory modulation of the B cells. In vitro, BTKi, as well as direct inhibition of B-cell mitochondrial respiration (but not glycolysis), limit the B-cell capacity to serve as APC to T cells. The role of metabolism in the regulation of human B-cell responses is confirmed when examining B cells of rare patients with mitochondrial respiratory chain mutations. We further demonstrate that both BTKi and metabolic modulation ex vivo can abrogate the aberrant activation and costimulatory molecule expression of B cells of untreated MS patients. Finally, as proof-of-principle in a Phase 1 study of healthy volunteers, we confirm that in vivo BTKi treatment reduces circulating B-cell mitochondrial respiration, diminishes their activation-induced expression of costimulatory molecules, and mediates an anti-inflammatory shift in the B-cell responses which is associated with an attenuation of T-cell pro-inflammatory responses. These data collectively elucidate a novel non-depleting mechanism by which BTKi mediates its effects on disease-implicated B-cell responses and reveals that modulating B-cell metabolism may be a viable therapeutic approach to target pro-inflammatory B cells.


Asunto(s)
Agammaglobulinemia Tirosina Quinasa , Linfocitos B , Esclerosis Múltiple , Inhibidores de Proteínas Quinasas , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Comunicación Celular , Humanos , Esclerosis Múltiple/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico
14.
Curr Opin Pediatr ; 32(6): 707-718, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33105273

RESUMEN

PURPOSE OF REVIEW: Primary mitochondrial disease is a highly heterogeneous but collectively common inherited metabolic disorder, affecting at least one in 4300 individuals. Therapeutic management of mitochondrial disease typically involves empiric prescription of enzymatic cofactors, antioxidants, and amino acid and other nutrient supplements, based on biochemical reasoning, historical experience, and consensus expert opinion. As the field continues to rapidly advance, we review here the preclinical and clinical evidence, and specific dosing guidelines, for common mitochondrial medicine therapies to guide practitioners in their prescribing practices. RECENT FINDINGS: Since publication of Mitochondrial Medicine Society guidelines for mitochondrial medicine therapies management in 2009, data has emerged to support consideration for using additional therapeutic agents and discontinuation of several previously used agents. Preclinical animal modeling data have indicated a lack of efficacy for vitamin C as an antioxidant for primary mitochondrial disease, but provided strong evidence for vitamin E and N-acetylcysteine. Clinical data have suggested L-carnitine may accelerate atherosclerotic disease. Long-term follow up on L-arginine use as prophylaxis against or acute treatment for metabolic strokes has provided more data supporting its clinical use in individuals with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome and Leigh syndrome. Further, several precision therapies have been developed for specific molecular causes and/or shared clinical phenotypes of primary mitochondrial disease. SUMMARY: We provide a comprehensive update on mitochondrial medicine therapies based on current evidence and our single-center clinical experience to support or refute their use, and provide detailed dosing guidelines, for the clinical management of mitochondrial disease. The overarching goal of empiric mitochondrial medicines is to utilize therapies with favorable benefit-to-risk profiles that may stabilize and enhance residual metabolic function to improve cellular resiliency and slow clinical disease progression and/or prevent acute decompensation.


Asunto(s)
Enfermedades Mitocondriales , Humanos , Enfermedades Mitocondriales/tratamiento farmacológico , Guías de Práctica Clínica como Asunto
15.
Artículo en Inglés | MEDLINE | ID: mdl-32431667

RESUMEN

The purpose of this investigational study was to assess the effects of melatonin replacement therapy on cardiac autonomic modulation in pinealectomized patients. This was an open-label, single-arm, single-center, proof-of-concept study consisting of a screening period, a 3-month treatment period with melatonin (3 mg/day), and a 6-month washout period. The cardiac autonomic function was determined through heart rate variability (HRV) measures during polysomnography. Pinealectomized patients (n = 5) with confirmed absence of melatonin were included in this study. Melatonin treatment increased vagal-dominated HRV indices including root mean square of the successive R-R interval differences (RMSSD) (39.7 ms, 95% CI 2.0-77.4, p = 0.04), percentage of successive R-R intervals that differ by more than 50 ms (pNN50) (17.1%, 95% CI 9.1-25.1, p = 0.003), absolute power of the high-frequency band (HF power) (1,390 ms2, 95% CI 511.9-2,267, p = 0.01), and sympathetic HRV indices like standard deviation of normal R-R wave interval (SDNN) (57.6 ms, 95% CI 15.2-100.0, p = 0.02), and absolute power of the low-frequency band (LF power) (4,592 ms2, 95% CI 895.6-8,288, p = 0.03). These HRV indices returned to pretreatment values when melatonin treatment was discontinued. The HRV entropy-based regularity parameters were not altered in this study, suggesting that there were no significant alterations of the REM-NREM ratios between the time stages of the study. These data show that 3 months of melatonin treatment may induce an improvement in cardiac autonomic modulation in melatonin-non-proficient patients. ClinicalTrials.gov Identifier: NCT03885258.


Asunto(s)
Sistema Nervioso Autónomo/fisiología , Corazón/fisiología , Melatonina/uso terapéutico , Pinealectomía/efectos adversos , Pinealoma/cirugía , Trastornos del Sueño-Vigilia/tratamiento farmacológico , Adolescente , Adulto , Sistema Nervioso Autónomo/efectos de los fármacos , Depresores del Sistema Nervioso Central/uso terapéutico , Niño , Femenino , Estudios de Seguimiento , Corazón/efectos de los fármacos , Frecuencia Cardíaca , Humanos , Masculino , Pronóstico , Trastornos del Sueño-Vigilia/etiología , Trastornos del Sueño-Vigilia/patología , Adulto Joven
16.
Curr Opin Neurol ; 32(5): 715-721, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31408013

RESUMEN

PURPOSE OF REVIEW: Although mitochondrial diseases impose a significant functional limitation in the lives of patients, treatment of these conditions has been limited to dietary supplements, exercise, and physical therapy. In the past few years, however, translational medicine has identified potential therapies for these patients. RECENT FINDINGS: For patients with primary mitochondrial myopathies, preliminary phase I and II multicenter clinical trials of elamipretide indicate safety and suggest improvement in 6-min walk test (6MWT) performance and fatigue scales. In addition, for thymidine kinase 2-deficient (TK2d) myopathy, compassionate-use oral administration of pyrimidine deoxynucleosides have shown preliminary evidence of safety and efficacy in survival of early onset patients and motor functions relative to historical TK2d controls. SUMMARY: The prospects of effective therapies that improve the quality of life for patients with mitochondrial myopathy underscore the necessity for definitive diagnoses natural history studies for better understanding of the diseases.


Asunto(s)
Miopatías Mitocondriales/tratamiento farmacológico , Oligopéptidos/uso terapéutico , Calidad de Vida , Ensayos Clínicos como Asunto , Ejercicio Físico/fisiología , Fatiga/fisiopatología , Humanos , Miopatías Mitocondriales/diagnóstico , Miopatías Mitocondriales/fisiopatología
17.
Biology (Basel) ; 8(2)2019 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-31083534

RESUMEN

The aging process includes impairment in mitochondrial function, a reduction in anti-oxidant activity, and an increase in oxidative stress, marked by an increase in reactive oxygen species (ROS) production. Oxidative damage to macromolecules including DNA and electron transport proteins likely increases ROS production resulting in further damage. This oxidative theory of cell aging is supported by the fact that diseases associated with the aging process are marked by increased oxidative stress. Coenzyme Q10 (CoQ10) levels fall with aging in the human but this is not seen in all species or all tissues. It is unknown whether lower CoQ10 levels have a part to play in aging and disease or whether it is an inconsequential cellular response to aging. Despite the current lay public interest in supplementing with CoQ10, there is currently not enough evidence to recommend CoQ10 supplementation as an anti-aging anti-oxidant therapy.

18.
Biology (Basel) ; 8(2)2019 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-31083577

RESUMEN

In recent years, several studies have examined the potential associations between mitochondrial dysfunction and neurodegenerative diseases such as multiple sclerosis (MS), Parkinson's disease and Alzheimer's disease. In MS, neurological disability results from inflammation, demyelination, and ultimately, axonal damage within the central nervous system. The sustained inflammatory phase of the disease leads to ion channel changes and chronic oxidative stress. Several independent investigations have demonstrated mitochondrial respiratory chain deficiency in MS, as well as abnormalities in mitochondrial transport. These processes create an energy imbalance and contribute to a parallel process of progressive neurodegeneration and irreversible disability. The potential roles of mitochondria in neurodegeneration are reviewed. An overview of mitochondrial diseases that may overlap with MS are also discussed, as well as possible therapeutic targets for the treatment of MS and other neurodegenerative conditions.

19.
Diabetes ; 68(5): 947-952, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30765337

RESUMEN

Melatonin, a pineal hormone synthesized at night, is critical for the synchronization of circadian and seasonal rhythms, being a key regulator of energy metabolism in many animal species. Although studies in humans are lacking, several reports, mainly on hibernating animals, demonstrated that melatonin supplementation and a short photoperiod increase brown adipose tissue (BAT) mass. The present proof-of-concept study is the first, to our knowledge, to evaluate BAT in patients with melatonin deficiency (radiotherapy or surgical removal of pineal gland) before and after daily melatonin (3 mg) replacement for 3 months. All four studied patients presented increased BAT volume and activity measured by positron emission tomography-MRI. We also found an improvement in total cholesterol and triglyceride blood levels without significant effects on body weight, liver fat, and HDL and LDL levels. Albeit not statistically significant, fasting insulin levels and HOMA of insulin resistance decreased in all four patients. The present results show that oral melatonin replacement increases BAT volume and activity and improves blood lipid levels in patients with melatonin deficiency, suggesting that melatonin is a possible BAT activator. Future studies are warranted because hypomelatoninemia is usually present in aging and appears as a result of light-at-night exposure and/or the use of ß-blocker drugs.


Asunto(s)
Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Melatonina/farmacología , Peso Corporal/efectos de los fármacos , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Metabolismo Energético/efectos de los fármacos , Femenino , Humanos , Masculino , Triglicéridos/sangre
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