RESUMEN
Subacute combined degeneration (SCD) is an acquired neurologic complication from prolonged vitamin B12 deficiency. As a result of dorsal and lateral spinal cord column degeneration, patients present with a range of neurological symptoms, including paresthesias, ataxia, and muscle weakness. Without prompt treatment, irreversible nerve damage occurs. Here we present a young man who developed progressive ascending paresthesias and lower extremity weakness after escalated nitrous oxide use. This case highlights the importance of considering SCD from nitrous oxide toxicity when patients present with progressive ataxia, paresthesia, and lower extremity weakness.
Asunto(s)
Enfermedades de la Médula Espinal , Degeneración Combinada Subaguda , Deficiencia de Vitamina B 12 , Masculino , Humanos , Óxido Nitroso/efectos adversos , Parestesia/inducido químicamente , Parestesia/complicaciones , Vitamina B 12/uso terapéutico , Deficiencia de Vitamina B 12/inducido químicamente , Deficiencia de Vitamina B 12/complicaciones , Deficiencia de Vitamina B 12/diagnóstico , Degeneración Combinada Subaguda/complicaciones , Enfermedades de la Médula Espinal/complicaciones , Ataxia/complicacionesRESUMEN
Typical retinitis pigmentosa (RP) may not be the only retinal phenotype encountered in ataxia with vitamin E deficiency (AVED). The following short case series describes a novel form of retinopathy in AVED. We describe two patients with AVED belonging to the same consanguineous sibship. Both presented an unusual retinopathy consisting of scattered, multifocal, nummular, hyperautofluorescent atrophic retinal patches. The retinopathy remained stable under vitamin E supplementation. We hypothesize these changes to be the result of arrested AVED-related RP following early supplementation with α-tocopherol acetate.
Asunto(s)
Retinitis Pigmentosa , Deficiencia de Vitamina E , Humanos , Proteínas Portadoras/genética , Ataxia/complicaciones , Ataxia/genética , Deficiencia de Vitamina E/complicaciones , Deficiencia de Vitamina E/genética , Retinitis Pigmentosa/complicaciones , Retinitis Pigmentosa/genética , Linaje , MutaciónRESUMEN
The aim of this consensus paper is to discuss the roles of the cerebellum in human gait, as well as its assessment and therapy. Cerebellar vermis is critical for postural control. The cerebellum ensures the mapping of sensory information into temporally relevant motor commands. Mental imagery of gait involves intrinsically connected fronto-parietal networks comprising the cerebellum. Muscular activities in cerebellar patients show impaired timing of discharges, affecting the patterning of the synergies subserving locomotion. Ataxia of stance/gait is amongst the first cerebellar deficits in cerebellar disorders such as degenerative ataxias and is a disabling symptom with a high risk of falls. Prolonged discharges and increased muscle coactivation may be related to compensatory mechanisms and enhanced body sway, respectively. Essential tremor is frequently associated with mild gait ataxia. There is growing evidence for an important role of the cerebellar cortex in the pathogenesis of essential tremor. In multiple sclerosis, balance and gait are affected due to cerebellar and spinal cord involvement, as a result of disseminated demyelination and neurodegeneration impairing proprioception. In orthostatic tremor, patients often show mild-to-moderate limb and gait ataxia. The tremor generator is likely located in the posterior fossa. Tandem gait is impaired in the early stages of cerebellar disorders and may be particularly useful in the evaluation of pre-ataxic stages of progressive ataxias. Impaired inter-joint coordination and enhanced variability of gait temporal and kinetic parameters can be grasped by wearable devices such as accelerometers. Kinect is a promising low cost technology to obtain reliable measurements and remote assessments of gait. Deep learning methods are being developed in order to help clinicians in the diagnosis and decision-making process. Locomotor adaptation is impaired in cerebellar patients. Coordinative training aims to improve the coordinative strategy and foot placements across strides, cerebellar patients benefiting from intense rehabilitation therapies. Robotic training is a promising approach to complement conventional rehabilitation and neuromodulation of the cerebellum. Wearable dynamic orthoses represent a potential aid to assist gait. The panel of experts agree that the understanding of the cerebellar contribution to gait control will lead to a better management of cerebellar ataxias in general and will likely contribute to use gait parameters as robust biomarkers of future clinical trials.
Asunto(s)
Ataxia Cerebelosa , Enfermedades Cerebelosas , Temblor Esencial , Humanos , Ataxia de la Marcha/etiología , Temblor , Consenso , Ataxia Cerebelosa/complicaciones , Ataxia/complicaciones , Enfermedades Cerebelosas/complicaciones , Marcha/fisiologíaRESUMEN
BACKGROUND: Wernicke encephalopathy (WE) is an acute neurological disease resulting from vitamin B1 deficiency, and there are only very few case reports of WE after liver transplantation. The present study aimed to investigate the clinical characteristics, etiology, magnetic resonance imaging (MRI) features, treatment and prognosis of patients with WE after liver transplantation. METHODS: Twenty-three patients with WE after liver transplantation from the First Affiliated Hospital, Zhejiang University School of Medicine and Jiangxi Provincial People's Hospital between January 2011 and December 2021 were retrospectively analyzed. RESULTS: Among the 23 patients diagnosed with WE after liver transplantation, 6 (26%) had a classic triad of impaired consciousness, oculomotor palsy and ataxia, and 17 (74%) had two features. The misdiagnosis rate was 65%. After treatment with high-dose vitamin B1, 19 (83%) patients showed improvement, whereas 4 (17%) showed no improvement, including 3 with residual short-term memory impairments and 1 with residual spatial and temporal disorientation and ataxia. CONCLUSIONS: The misdiagnosis rate is high in the early stage of WE, and the prognosis is closely associated with whether WE is diagnosed early and treated timely. High-dose glucose or glucocorticoids can trigger WE and cannot be administered before vitamin B1 treatment. Vitamin B1 is suggested to be used as a prophylactic treatment for patients with WE after liver transplantation.
Asunto(s)
Trasplante de Hígado , Encefalopatía de Wernicke , Humanos , Encefalopatía de Wernicke/diagnóstico , Encefalopatía de Wernicke/tratamiento farmacológico , Encefalopatía de Wernicke/etiología , Trasplante de Hígado/efectos adversos , Estudios Retrospectivos , Tiamina/uso terapéutico , Imagen por Resonancia Magnética , Ataxia/complicaciones , Ataxia/tratamiento farmacológicoRESUMEN
INTRODUCTION: Primary coenzyme Q10 (CoQ10) deficiency, a recessive disorder associated with various defects of CoQ10 biosynthesis and widely varying clinical presentation, is customarily managed by oral Q10 supplementation but the benefit is debated. METHODS: To address this question, we mapped individual responses in two patients with COQ8A-related ataxia following coenzyme Q10 supplementation using noninvasive imaging. Metabolic 31phosphorus magnetic resonance spectroscopy imaging (31P-MRSI) and volumetric cerebellar neuroimaging were performed to quantify the individual treatment response in two patients with COQ8A-related ataxia, each compared with eight age- and gender-matched healthy control subjects. RESULTS: Post-treatment change in energy metabolite levels differed in the two patients, with higher energy levels and improved dysarthria and leg coordination in one, and decreased energy levels without clinical benefit in the other. CONCLUSIONS: Our results suggest that the cerebellar bioenergetic state may predict treatment response in COQ8A-related ataxia and highlight the potential of pathophysiology-orientated neuroimaging evidence to inform treatment decisions.
Asunto(s)
Ataxia Cerebelosa , Enfermedades Mitocondriales , Ataxia/complicaciones , Ataxia/diagnóstico por imagen , Ataxia/tratamiento farmacológico , Ataxia Cerebelosa/complicaciones , Ataxia Cerebelosa/diagnóstico por imagen , Ataxia Cerebelosa/tratamiento farmacológico , Metabolismo Energético , Humanos , Enfermedades Mitocondriales/complicaciones , Debilidad Muscular/complicaciones , Ubiquinona/deficiencia , Ubiquinona/uso terapéuticoRESUMEN
OBJECTIVE: To assess outcomes of children with functional constipation after antegrade continence enemas (ACEs) and determine if pre operative anorectal manometry (AMAN) findings, including dyssynergic defecation, are associated with outcomes. METHODS: A retrospective review of pediatric patients with functional constipation who received a Malone appendicostomy or cecostomy after failed medical management was conducted. Patients were included if they had AMAN data prior to their operation. Patients that underwent colonic resection were excluded. Demographics, clinical characteristics, manometry results, and post ACE outcomes were obtained. Descriptive statistics were performed. RESULTS: Thirty-nine patients were identified with median age at ACE of 8.9 years (IQR: 7.2-12.6) and median follow-up of 2.5 years (IQR: 1.8-3.2 years). Twenty patients (51%) were female and most (35, 92%) were White. All patients had severe constipation prior to ACE and 59% had fecal incontinence. Thirty-four patients (87%) received a Malone and 5 (13%) received a cecostomy. Post ACE, 35 (90%) were clean with daily flushes and 6 (15%) eventually successfully transitioned to laxatives only. Awake AMAN and balloon expulsion test were performed in 15 patients, with 14 (93%) displaying evidence of dyssynergic defecation. Twelve of 14 of patients (86%) with dyssynergia were clean with ACE at follow-up. because of the majority of patients being clean post ACE, there was limited power to detect predictors of poor outcomes. CONCLUSIONS: ACEs are successful treatment options for patients with severe constipation and fecal incontinence, including those with dyssynergic defecation. Larger studies are needed to identify factors predictive of poor outcomes. LEVEL OF EVIDENCE: III.
Asunto(s)
Incontinencia Fecal , Amantadina , Ataxia/complicaciones , Niño , Estreñimiento/etiología , Estreñimiento/cirugía , Defecación , Enema/métodos , Incontinencia Fecal/etiología , Incontinencia Fecal/cirugía , Femenino , Humanos , Masculino , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVE: To investigate the effects of concomitant injections of botulinum toxin-A (BoNT-A) into the detrusor and external urethral sphincter muscles in suprasacral spinal cord injured patients with detrusor overactivity and detrusor sphincter dyssynergia. DESIGN: An open treatment trial with pre- and posttreatment evaluations. SUBJECTS: Male suprasacral spinal cord injury patients (n = 20) with neurogenic detrusor overactivity and detrusor sphincter dyssynergia who emptied their bladder by reflex voiding and were unwilling to increase the frequency of intermittent catheterization. METHODS: Cystoscopic guidance of 200 U BoNT-A injections into the detrusor muscle and 100 U into external urethral sphincter muscles were applied. The urodynamic parameters, voiding diaries and quality of life scores using Urinary Distress Inventory, Short Form (UDI-6) and Incontinence Impact Questionnaire, Short Form (IIQ-7) were compared. RESULTS: All participants experienced a significant mean reduction in maximal detrusor pressure and maximal urethral pressure profile, and a mean significant increase in maximal cystometric bladder capacity 12 weeks after concomitant injections. Bladder diaries demonstrated persistently increased spontaneous voided volume, but no increase in post-void residual ratio, daily clean intermittent catheterization (CIC) frequency and diaper pad use from baseline to 24 weeks. UDI-6 scores were significantly improved at 4 and 12 weeks and IIQ-7 scores improved only at 12 weeks. CONCLUSION: Concomitant detrusor and external urethral sphincter BoNT-A injections may decrease detrusor and urethral pressure without increasing postvoid residual ratio and diaper pad use. For spinal cord injury patients with neurogenic detrusor overactivity and detrusor sphincter dyssynergia who are unwilling, or for whom it is inconvenient, to increase CIC frequency and who want to preserve spontaneous voiding, this treatment may provide an optional alternative.
Asunto(s)
Toxinas Botulínicas Tipo A , Traumatismos de la Médula Espinal , Ataxia/complicaciones , Toxinas Botulínicas Tipo A/uso terapéutico , Humanos , Masculino , Calidad de Vida , Traumatismos de la Médula Espinal/complicaciones , Resultado del Tratamiento , UretraRESUMEN
BACKGROUND: A small amount of methanol is produced endogenously in the human body but it is efficiently metabolized by alcohol dehydrogenase (ADH) and other enzymes, and the products eliminated without harm. In this study, we present a new entity of inborn error of methanol metabolism due to a mutation in the ADH1C gene coding for the γ subunit that is part of several ADH isoenzymes. RESULTS: This disorder was discovered in an 11.58-year-old boy. During one 9-month hospital admission, he had periods of 1-4 days during which he was comatose, and between these periods he was sometimes verbose and euphoric, and had ataxia, dysarthria. Following hemodialysis treatments, he became conscious and appeared healthy. Organ evaluations and his laboratory tests were normal. Toxicological evaluation of his blood showed a high methanol level [12.2 mg/dL (3.8 mmol/L), normal range up to 3.5 mg/dL (1.09 mmol/L) while the formaldehyde level was undetectable. The finding of liver function tests that were within normal limits, coupled with a normal eye examination and size of the liver, elevated blood methanol levels and an undetectable formaldehyde level, suggested ADH insufficiency. Adding zinc to the drug regimen 15 mg/daily dramatically reduced the patient's methanol level and alleviated the abnormal symptoms. When zinc supplementation was discontinued, the patient relapsed into a coma and hemodialysis was once again required. A homozygous mutation in ADH1C gene located at exon 3 was found, and both parents were heterozygous for this mutation. CONCLUSION: Accumulation of methanol due to mutation in ADH1C gene may result in drunkenness and ataxia, and leads to coma. This condition can be successfully treated with zinc supplementation as the cofactor of ADH.
Asunto(s)
Alcohol Deshidrogenasa/genética , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/genética , Metanol/sangre , Alcohol Deshidrogenasa/metabolismo , Intoxicación Alcohólica/complicaciones , Ataxia/complicaciones , Niño , Coma/etiología , Exones/genética , Heterocigoto , Humanos , Hígado/metabolismo , Masculino , Enfermedades Metabólicas/diagnóstico , Enfermedades Metabólicas/genética , Errores Innatos del Metabolismo/complicaciones , Errores Innatos del Metabolismo/terapia , Metanol/metabolismo , Mutación , Diálisis Renal/métodos , Resultado del Tratamiento , Zinc/administración & dosificaciónRESUMEN
Coenzyme Q10 (CoQ10) is a ubiquitous cofactor in the body, operating in the inner mitochondrial membrane, where it plays a vital role in the generation of adenosine triphosphate (ATP) through the electron transport chain (ETC). In addition to this, CoQ10 serves as an antioxidant, protecting the cell from oxidative stress by reactive oxygen species (ROS) as well as maintaining a proton (H+) gradient across lysosome membranes to facilitate the breakdown of cellular waste products. Through the process of ageing, the body becomes deficient in CoQ10, resulting in several systemic manifestations. On a cellular level, one of the consequences of CoQ10 deficiency is apoptosis, which can be visualised in tissues of the central nervous system (CNS). Diseases affecting the retina and brain such as age-related macular degeneration (AMD), glaucoma, Alzheimer's disease (AD) and Parkinson's disease (PD) have shown defects in cellular biochemical reactions attributed to reduced levels of CoQ10. Through further research into the pathogenesis of such conditions, the effects of CoQ10 deficiency can be counteracted through supplementation, early detection and intervention.
Asunto(s)
Ataxia/metabolismo , Encéfalo/metabolismo , Enfermedades Mitocondriales/metabolismo , Debilidad Muscular/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Retina/metabolismo , Ubiquinona/deficiencia , Animales , Ataxia/complicaciones , Ataxia/patología , Encéfalo/patología , Humanos , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/patología , Debilidad Muscular/complicaciones , Debilidad Muscular/patología , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/patología , Retina/patología , Ubiquinona/análogos & derivados , Ubiquinona/metabolismoRESUMEN
While rehabilitation therapies always help patients with ataxia, there are currently no FDA-approved treatments for ataxia. Medications are available to treat symptoms that may complicate an ataxic illness, e.g., tremor, myoclonus, dystonia, and rigidity, which are discussed elsewhere in this volume. Spasticity, pain, fatigue, depression, sleep disturbances, cognitive decline, and bowel and bladder dysfunction, if they occur, all have multiple available drugs and therapies for symptomatic use. There is also an extensive literature on off-label uses of various medications to improve imbalance. The pipeline of emerging therapies for symptomatic and possible disease-modifying management of ataxia gives hope that we will soon see the first of many FDA-approved drugs for ataxic illnesses.
Asunto(s)
Ataxia/diagnóstico , Ataxia/terapia , Animales , Antiinflamatorios/uso terapéutico , Ataxia/complicaciones , Ensayos Clínicos como Asunto/métodos , Terapia por Estimulación Eléctrica/métodos , Terapia por Ejercicio/métodos , Fatiga/diagnóstico , Fatiga/etiología , Fatiga/terapia , Humanos , Fármacos Neuroprotectores/uso terapéutico , Dolor/diagnóstico , Dolor/etiología , Resultado del Tratamiento , Temblor/diagnóstico , Temblor/etiología , Temblor/terapiaRESUMEN
Marked elevation in the brain concentration of N-acetyl-L-aspartate (NAA) is a characteristic feature of Canavan disease, a vacuolar leukodystrophy resulting from deficiency of the oligodendroglial NAA-cleaving enzyme aspartoacylase. We now demonstrate that inhibiting NAA synthesis by intracisternal administration of a locked nucleic acid antisense oligonucleotide to young-adult aspartoacylase-deficient mice reverses their pre-existing ataxia and diminishes cerebellar and thalamic vacuolation and Purkinje cell dendritic atrophy. Ann Neurol 2020;87:480-485.
Asunto(s)
Ácido Aspártico/análogos & derivados , Enfermedad de Canavan/tratamiento farmacológico , Oligonucleótidos Antisentido/uso terapéutico , Acetiltransferasas/antagonistas & inhibidores , Amidohidrolasas/deficiencia , Amidohidrolasas/genética , Animales , Ácido Aspártico/biosíntesis , Ataxia/complicaciones , Ataxia/tratamiento farmacológico , Atrofia/complicaciones , Atrofia/tratamiento farmacológico , Enfermedad de Canavan/complicaciones , Enfermedad de Canavan/patología , Cerebelo/patología , Femenino , Técnicas de Silenciamiento del Gen , Infusiones Intraventriculares , Masculino , Ratones , Mutación , Oligonucleótidos Antisentido/administración & dosificación , Células de Purkinje/patología , Prueba de Desempeño de Rotación con Aceleración Constante , Tálamo/patología , Vacuolas/efectos de los fármacos , Vacuolas/patologíaRESUMEN
Cerebellar ataxia is a hallmark of coenzyme Q10 (CoQ10) deficiency associated with COQ8A mutations. We present four patients, one with novel COQ8A pathogenic variants all with early, prominent handwriting impairment, dystonia and only mild ataxia. To better define the phenotypic spectrum and course of COQ8A disease, we review the clinical presentation and evolution in 47 reported cases. Individuals with COQ8A mutation display great clinical variability and unpredictable responses to CoQ10 supplementation. Onset is typically during infancy or childhood with ataxic features associated with developmental delay or regression. When disease onset is later in life, first symptoms can include: incoordination, epilepsy, tremor, and deterioration of writing. The natural history is characterized by a progression to a multisystem brain disease dominated by ataxia, with disease severity inversely correlated with age at onset. Six previously reported cases share with ours, a clinical phenotype characterized by slowly progressive or static writing difficulties, focal dystonia, and speech disorder, with only minimal ataxia. The combination of writing difficulty, dystonia and ataxia is a distinctive constellation that is reminiscent of a previously described clinical entity called Dystonia Ataxia Syndrome (DYTCA) and is an important clinical indicator of COQ8A mutations, even when ataxia is mild or absent.
Asunto(s)
Ataxia , Progresión de la Enfermedad , Trastornos Distónicos , Escritura Manual , Heterocigoto , Enfermedades Mitocondriales , Proteínas Mitocondriales/genética , Debilidad Muscular , Ubiquinona/deficiencia , Adulto , Ataxia/complicaciones , Ataxia/epidemiología , Ataxia/etiología , Ataxia/genética , Ataxia/fisiopatología , Niño , Trastornos Distónicos/epidemiología , Trastornos Distónicos/etiología , Trastornos Distónicos/genética , Trastornos Distónicos/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/epidemiología , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/fisiopatología , Debilidad Muscular/complicaciones , Debilidad Muscular/epidemiología , Debilidad Muscular/genética , Debilidad Muscular/fisiopatología , Ubiquinona/genética , Adulto JovenRESUMEN
OBJECTIVES: Biofeedback therapy, whether administered at home or in office settings, is effective for dyssynergic defecation (DD). Whether home biofeedback improves quality of life (QOL) and is cost-effective when compared with office biofeedback is unknown. METHODS: QOL was assessed in 8 domains (SF-36) at baseline and after treatment (3 months), alongside economic evaluation during a randomized controlled trial (RCT) comparing home and office biofeedback in patients with DD (Rome III). Costs related to both biofeedback programs were estimated from the hospital financial records, study questionnaires, and electronic medical records. A conversion algorithm (Brazier) was used to calculate the patient's quality-adjusted life years (QALYs) from SF-36 responses. Cost-effectiveness was expressed as incremental costs per QALY between the treatment arms. RESULTS: One hundred patients (96 female patients, 50 in each treatment arm) with DD participated. Six of the 8 QOL domains improved (P < 0.05) in office biofeedback, whereas 4 of the 8 domains improved (P < 0.05) in home biofeedback; home biofeedback was noninferior to office biofeedback. The median cost per patient was significantly lower (P < 0.01) for home biofeedback ($1,112.39; interquartile range (IQR), $826-$1,430) than for office biofeedback ($1,943; IQR, $1,622-$2,369), resulting in a cost difference of $830.11 The median QALY gained during the trial was 0.03 for office biofeedback and 0.07 for home biofeedback (P = NS). The incremental cost-effectiveness ratio was $20,752.75 in favor of home biofeedback. DISCUSSION: Biofeedback therapy significantly improves QOL in patients with DD regardless of home or office setting. Home biofeedback is a cost-effective treatment option for DD compared with office biofeedback, and it offers the potential of treating many more patients in the community.
Asunto(s)
Ataxia/complicaciones , Biorretroalimentación Psicológica/métodos , Estreñimiento/terapia , Defecación/fisiología , Calidad de Vida , Adolescente , Adulto , Anciano , Ataxia/economía , Ataxia/terapia , Estreñimiento/economía , Estreñimiento/etiología , Análisis Costo-Beneficio , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
COQ4 mutations have recently been shown to cause a broad spectrum of mitochondrial disorders in association with CoQ10 deficiency. Herein, we report the clinical phenotype, in silico and biochemical analyses, and intervention for a novel c.370 G > A (p.G124S) COQ4 mutation in a Chinese family. This mutation is exclusively present in the East Asian population (allele frequency of ~0.001). The homozygous mutation caused CoQ10 deficiency-associated Leigh syndrome with an onset at 1-2 months of age, presenting as respiratory distress, lactic acidosis, dystonia, seizures, failure to thrive, and detectable lesions in the midbrain and basal ganglia. No renal impairment was involved. The levels of CoQ10 and mitochondrial respiratory chain complex (C) II + III activity were clearly lower in cultured fibroblasts derived from the patient than in those from unaffected carriers; the decreased CII + III activity could be increased by CoQ10 treatment. Follow-up studies suggested that our patient benefitted from the oral supplementation of CoQ10, which allowed her to maintain a relatively stable health status. Based on the genetic testing, preimplantation and prenatal diagnoses were performed, confirming that the next offspring of this family was unaffected. Our cases expand the phenotypic spectrum of COQ4 mutations and the genotypic spectrum of Leigh syndrome.
Asunto(s)
Ataxia/genética , Pruebas Genéticas , Enfermedad de Leigh/genética , Enfermedades Mitocondriales/genética , Proteínas Mitocondriales/genética , Debilidad Muscular/genética , Ubiquinona/deficiencia , Pueblo Asiatico/genética , Ataxia/complicaciones , Preescolar , Simulación por Computador , Femenino , Fibroblastos/metabolismo , Heterocigoto , Homocigoto , Humanos , Lactante , Enfermedad de Leigh/complicaciones , Enfermedad de Leigh/fisiopatología , Masculino , Mitocondrias/genética , Mitocondrias/patología , Enfermedades Mitocondriales/complicaciones , Debilidad Muscular/complicaciones , Mutación , Fenotipo , Ubiquinona/genética , Ubiquinona/farmacocinéticaRESUMEN
OBJECTIVE: To examine the effects of bowel management on urinary incontinence in patients with spina bifida associated with overactive bladder (OAB) and detrusor sphincter dyssynergia (DSD). MATERIALS AND METHODS: The research was carried out during the period 2014-2017. A total of 35 patients (group 1) were administered bowel management combined with anticholinergic medication therapy and clean intermittent catheterization (CIC) and 35 patients (group 2) were treated only with anticholinergic medication therapy and CIC. Bowel management included daily enema, laxative application and a special diet, with the aim of treating constipation, evaluated according to the Roma III criteria and echosonographically determined transversal rectal diameter. The effects of the administered bowel management on urinary incontinence were assessed according to the mean dry interval between two CICs for all patients. All patients were followed up for 1 year, during which data were prospectively collected. RESULTS: There was no statistically significant difference with regard to age, gender and baseline clinical features between the two groups. In group 1, the mean ± sd dry interval between two CICs was 150.0 ± 36.4 min, and group 2 it was 101.3 ± 51.6 min. There was a significant difference in urinary incontinence, i.e. in the mean dry interval, between the two groups (P < 0.001). CONCLUSION: Administering bowel management considerably increased the mean dry interval, thus greatly alleviating the symptoms of urinary incontinence. For this reason, bowel management should form an integral part of the treatment of patients with spina bifida and OAB and DSD.
Asunto(s)
Ataxia/complicaciones , Estreñimiento/terapia , Disrafia Espinal/complicaciones , Vejiga Urinaria Hiperactiva/complicaciones , Incontinencia Urinaria/etiología , Incontinencia Urinaria/terapia , Adolescente , Niño , Preescolar , Antagonistas Colinérgicos/uso terapéutico , Estreñimiento/complicaciones , Dieta , Enema , Femenino , Estudios de Seguimiento , Humanos , Cateterismo Uretral Intermitente , Laxativos/uso terapéutico , Masculino , Estudios Prospectivos , Adulto JovenRESUMEN
BACKGROUND: COQ2 mutations cause a rare infantile multisystemic disease with heterogeneous clinical features. Promising results have been reported in response to Coenzyme Q10 treatment, especially for kidney involvement, but little is known about the long-term outcomes. METHODS: We report four new patients from two families with the c.437GâA (p.Ser146Asn) mutation in COQ2 and the outcomes of two patients after long-term coenzyme Q10 treatment. RESULTS: Index cases from two families presented with vomiting, nephrotic range proteinuria, and diabetes in early infancy. These patients were diagnosed with coenzyme Q10 deficiency and died shortly after diagnosis. Siblings of the index cases later presented with neonatal diabetes and proteinuria and were diagnosed at the first day of life. Coenzyme Q10 treatment was started immediately. The siblings responded dramatically to coenzyme Q10 treatment with normalized glucose and proteinuria levels, but they developed refractory focal clonic seizures beginning at three months of life that progressed to encephalopathy. CONCLUSIONS: In our cohort with CoQ10 deficiency, neurological involvement did not improve with oral coenzyme Q10 treatment despite the initial recovery from the diabetes and nephrotic syndrome.
Asunto(s)
Proteínas Adaptadoras del Transporte Vesicular/genética , Ataxia/dietoterapia , Ataxia/genética , Enfermedades Mitocondriales/dietoterapia , Enfermedades Mitocondriales/genética , Debilidad Muscular/dietoterapia , Debilidad Muscular/genética , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Ataxia/complicaciones , Ataxia/diagnóstico por imagen , Estudios de Cohortes , Diabetes Mellitus/etiología , Salud de la Familia , Femenino , Humanos , Lactante , Riñón/patología , Riñón/ultraestructura , Imagen por Resonancia Magnética , Masculino , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/diagnóstico por imagen , Debilidad Muscular/complicaciones , Debilidad Muscular/diagnóstico por imagen , Mutación/genética , Proteinuria/etiología , Ubiquinona/genética , Ubiquinona/uso terapéuticoRESUMEN
Familial Hypercholesterolemia (FH) is an autosomal co-dominant genetic disorder characterized by elevated low-density lipoprotein (LDL) cholesterol levels and increased risk for premature cardiovascular disease. Here, we examined FH pathophysiology in skin fibroblasts derived from FH patients harboring heterozygous mutations in the LDL-receptor. Fibroblasts from FH patients showed a reduced LDL-uptake associated with increased intracellular cholesterol levels and coenzyme Q10 (CoQ10) deficiency, suggesting dysregulation of the mevalonate pathway. Secondary CoQ10 deficiency was associated with mitochondrial depolarization and mitophagy activation in FH fibroblasts. Persistent mitophagy altered autophagy flux and induced inflammasome activation accompanied by increased production of cytokines by mutant cells. All the pathological alterations in FH fibroblasts were also reproduced in a human endothelial cell line by LDL-receptor gene silencing. Both increased intracellular cholesterol and mitochondrial dysfunction in FH fibroblasts were partially restored by CoQ10 supplementation. Dysregulated mevalonate pathway in FH, including increased expression of cholesterogenic enzymes and decreased expression of CoQ10 biosynthetic enzymes, was also corrected by CoQ10 treatment. Reduced CoQ10 content and mitochondrial dysfunction may play an important role in the pathophysiology of early atherosclerosis in FH. The diagnosis of CoQ10 deficiency and mitochondrial impairment in FH patients may also be important to establish early treatment with CoQ10.
Asunto(s)
Ataxia/complicaciones , Colesterol/metabolismo , Fibroblastos/patología , Hiperlipoproteinemia Tipo II/complicaciones , Enfermedades Mitocondriales/complicaciones , Debilidad Muscular/complicaciones , Ubiquinona/deficiencia , Ataxia/metabolismo , Ataxia/patología , Células Cultivadas , Fibroblastos/metabolismo , Humanos , Hiperlipoproteinemia Tipo II/metabolismo , Hiperlipoproteinemia Tipo II/patología , Lipoproteínas LDL/metabolismo , Potencial de la Membrana Mitocondrial , Mitocondrias/metabolismo , Mitocondrias/patología , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Mitofagia , Debilidad Muscular/metabolismo , Debilidad Muscular/patología , Especies Reactivas de Oxígeno/metabolismo , Receptores de LDL/metabolismo , Ubiquinona/metabolismoRESUMEN
Nephrotic syndrome (NS), a frequent chronic kidney disease in children and young adults, is the most common phenotype associated with primary coenzyme Q10 (CoQ10) deficiency and is very responsive to CoQ10 supplementation, although the pathomechanism is not clear. Here, using a mouse model of CoQ deficiency-associated NS, we show that long-term oral CoQ10 supplementation prevents kidney failure by rescuing defects of sulfides oxidation and ameliorating oxidative stress, despite only incomplete normalization of kidney CoQ levels and lack of rescue of CoQ-dependent respiratory enzymes activities. Liver and kidney lipidomics, and urine metabolomics analyses, did not show CoQ metabolites. To further demonstrate that sulfides metabolism defects cause oxidative stress in CoQ deficiency, we show that silencing of sulfide quinone oxido-reductase (SQOR) in wild-type HeLa cells leads to similar increases of reactive oxygen species (ROS) observed in HeLa cells depleted of the CoQ biosynthesis regulatory protein COQ8A. While CoQ10 supplementation of COQ8A depleted cells decreases ROS and increases SQOR protein levels, knock-down of SQOR prevents CoQ10 antioxidant effects. We conclude that kidney failure in CoQ deficiency-associated NS is caused by oxidative stress mediated by impaired sulfides oxidation and propose that CoQ supplementation does not significantly increase the kidney pool of CoQ bound to the respiratory supercomplexes, but rather enhances the free pool of CoQ, which stabilizes SQOR protein levels rescuing oxidative stress.
Asunto(s)
Antioxidantes/farmacología , Ataxia/tratamiento farmacológico , Sulfuro de Hidrógeno/metabolismo , Enfermedades Mitocondriales/tratamiento farmacológico , Debilidad Muscular/tratamiento farmacológico , Síndrome Nefrótico/tratamiento farmacológico , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Transferasas Alquil y Aril/genética , Animales , Antioxidantes/uso terapéutico , Ataxia/complicaciones , Ataxia/metabolismo , Modelos Animales de Enfermedad , Células HeLa , Humanos , Riñón/metabolismo , Riñón/patología , Redes y Vías Metabólicas/efectos de los fármacos , Ratones , Ratones Transgénicos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/metabolismo , Debilidad Muscular/complicaciones , Debilidad Muscular/metabolismo , Síndrome Nefrótico/etiología , Síndrome Nefrótico/metabolismo , Síndrome Nefrótico/patología , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ubiquinona/metabolismo , Ubiquinona/farmacología , Ubiquinona/uso terapéuticoRESUMEN
BACKGROUND: Nephrotic syndrome can be caused by a subgroup of mitochondrial diseases classified as primary coenzyme Q10 (CoQ10) deficiency. Pathogenic COQ2 variants are a cause of primary CoQ10 deficiency and present with phenotypes ranging from isolated nephrotic syndrome to fatal multisystem disease. CASE-DIAGNOSIS/TREATMENT: We report three pediatric patients with COQ2 variants presenting with nephrotic syndrome. Two of these patients had normal leukocyte CoQ10 levels prior to treatment. Pathologic findings varied from mesangial sclerosis to focal segmental glomerulosclerosis, with all patients having abnormal appearing mitochondria on kidney biopsy. In two of the three patients treated with CoQ10 supplementation, the nephrotic syndrome resolved; and at follow-up, both have normal renal function and stable proteinuria. CONCLUSIONS: COQ2 nephropathy should be suspected in patients presenting with nephrotic syndrome, although less common than disease due to mutations in NPHS1, NPHS2, and WT1. The index of suspicion should remain high, and we suggest that providers consider genetic evaluation even in patients with normal leukocyte CoQ10 levels, as levels may be within normal range even with significant clinical disease. Early molecular diagnosis and specific treatment are essential in the management of this severe yet treatable condition.
Asunto(s)
Transferasas Alquil y Aril/genética , Ataxia/tratamiento farmacológico , Enfermedades Mitocondriales/tratamiento farmacológico , Debilidad Muscular/tratamiento farmacológico , Síndrome Nefrótico/terapia , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Ataxia/complicaciones , Ataxia/diagnóstico , Ataxia/genética , Biopsia , Niño , Preescolar , Pruebas Genéticas , Humanos , Riñón/patología , Trasplante de Riñón , Masculino , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , Debilidad Muscular/complicaciones , Debilidad Muscular/diagnóstico , Debilidad Muscular/genética , Síndrome Nefrótico/sangre , Síndrome Nefrótico/diagnóstico , Síndrome Nefrótico/etiología , Resultado del Tratamiento , Ubiquinona/administración & dosificación , Ubiquinona/genéticaRESUMEN
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