RESUMO
BACKGROUND: TBL1XR1 encodes a F-box-like/WD40 repeat-containing protein that plays a role in transcription mediated by nuclear receptors and is a known genetic cause of neurodevelopmental disease of childhood (OMIM# 608628). Yet the developmental trajectory and progression of neurologic symptoms over time remains poorly understood. METHODS: We developed and distributed a survey to two closed Facebook groups devoted to families of patients with TBL1XR1-related disorder. The survey consisted of 14 subsections focused upon the developmental trajectories of cognitive, behavioral, motor, and other neurological abnormalities. Data were collected and managed using REDCap electronic data capture tools. RESULTS: Caregivers of 41 patients with a TBL1XR1-related disorder completed the cross-sectional survey. All reported variants affecting a single amino acid, including missense mutations and in-frame deletions, were found in the WD40 repeat regions of Tbl1xr1. These are domains considered important for protein-protein interactions that may plausibly underlie disease pathology. The majority of patients were diagnosed with a neurologic condition before they received their genetic diagnosis. Language appeared most significantly affected with only a minority of the cohort achieving more advanced milestones in this domain. CONCLUSION: TBL1XR1-related disorder encompasses a spectrum of clinical presentations, marked by early developmental delay ranging in severity, with a subset of patients experiencing developmental regression in later childhood.
Assuntos
Transtornos do Neurodesenvolvimento , Humanos , Estudos Transversais , Mutação de Sentido Incorreto/genética , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Repressoras/genéticaRESUMO
CONTEXT: Males with adrenoleukodystrophy (ALD) have an 80% lifetime risk of developing adrenal insufficiency (AI), which can be life-threatening when undetected. Newborn screening (NBS) for ALD has been implemented in 29 states, yet the impact of NBS upon clinical management has not been reported. OBJECTIVE: To investigate whether the implementation of NBS has altered the time to diagnosis of AI in children with ALD. DESIGN: We conducted a retrospective medical chart review of pediatric patients with ALD. SETTING: All patients were seen in a leukodystrophy clinic in an academic medical center. PATIENTS: We included all pediatric patients with ALD who were seen between May 2006 and January 2022. We identified 116 patients (94% boys). MAIN OUTCOME MEASURES: We extracted information about ALD diagnosis in all patients and AI surveillance, diagnosis, and treatment in boys with ALD. RESULTS: Thirty-one (27%) patients were diagnosed with ALD by NBS, and 85 (73%) were diagnosed outside the newborn period. The prevalence of AI among boys in our patient population was 74%. AI diagnosis was made significantly earlier in boys diagnosed with ALD by NBS than in boys diagnosed outside the newborn period (median [IQR] age of diagnosis = 6.7 [3.9, 12.12] months vs 6.05 [3.74, 8.35] years) (P < .001). When maintenance dose of glucocorticoids were initiated, there were significant differences in ACTH and peak cortisol levels in patients diagnosed by NBS and outside the newborn period. CONCLUSIONS: Our results suggest that implementing NBS for ALD leads to significantly earlier detection of AI and earlier initiation of glucocorticoid supplementation in boys affected by ALD.
Assuntos
Insuficiência Adrenal , Adrenoleucodistrofia , Masculino , Recém-Nascido , Humanos , Criança , Feminino , Adrenoleucodistrofia/diagnóstico , Adrenoleucodistrofia/epidemiologia , Estudos Retrospectivos , Triagem Neonatal/métodos , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/epidemiologia , Diagnóstico PrecoceRESUMO
OBJECTIVE: To characterize the prevalence, onset, and burden of urinary and bowel dysfunction in adult patients with adrenoleukodystrophy (ALD) and to evaluate any sex differences in symptom presentation. METHODS: In this retrospective and prospective study, we performed medical record review (n = 103), analyzed the results of clinically indicated urodynamic testing (n = 11), and developed and distributed a symptom and quality of life (QOL) survey (n = 59). RESULTS: Urinary and bowel symptoms are highly prevalent in both males (75.0%) and females (78.8%) in this population, most commonly urinary urgency, often leading to incontinence. Time to onset of first urinary or bowel symptom occurs approximately a decade earlier in males. Seventy-two percent of symptomatic patients report a limitation to QOL. Urodynamic evaluation provides evidence of three distinct mechanisms underlying lower urinary tract dysfunction: involuntary detrusor contractions (indicating uncontrolled neuronal stimulation with or without leakage), motor underactivity of the bladder, and asynergy between detrusor contraction and sphincter relaxation. CONCLUSIONS: Beyond gait and balance difficulties, urinary and bowel symptoms are common in adults with ALD and impair QOL. Males are affected at a younger age but both sexes experience a higher symptom burden with age. As this population also experiences gait and balance impairment, patients with ALD are more vulnerable to urinary urgency leading to incontinence. Urodynamic evaluation may help better elucidate the pathophysiologic mechanisms underlying neurogenic lower urinary tract dysfunction, which can allow more targeted treatment.
Assuntos
Adrenoleucodistrofia , Sistema Urinário , Adulto , Feminino , Marcha , Humanos , Masculino , Estudos Prospectivos , Qualidade de Vida , Estudos RetrospectivosRESUMO
Leukodystrophies are a group of neurodegenerative genetic disorders that affect approximately 1 in 7500 individuals. Despite therapeutic progress in individual leukodystrophies, guidelines in neurologic care are sparse and consensus among physicians and caregivers remains a challenge. At patient advocacy meetings hosted by Hunter's Hope from 2016-2018, multidisciplinary experts and caregivers met to conduct a literature review, identify knowledge gaps and summarize best practices regarding neurologic care. Stages of severity in leukodystrophies guided recommendations to address different levels of need based on a newly defined system of disease severity. Four core neurologic domains prioritized by families were identified and became the focus of this guideline: sleep, pain, seizures/epilepsy, and language/cognition. Based on clinical severity, the following categories were used: presymptomatic, early symptomatic, intermediate symptomatic, and advanced symptomatic. Across the leukodystrophies, neurologic care should be tailored to stages of severity while accounting for unique aspects of every disease and multiple knowledge gaps present. Standardized tools and surveys can help guide treatment but should not overburden families.
Assuntos
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/terapia , Criança , Humanos , Defesa do Paciente , Guias de Prática Clínica como Assunto , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Among boys with X-Linked adrenoleukodystrophy, a subset will develop childhood cerebral adrenoleukodystrophy (CCALD). CCALD is typically lethal without hematopoietic stem cell transplant before or soon after symptom onset. We sought to establish evidence-based guidelines detailing the neuroimaging surveillance of boys with neurologically asymptomatic adrenoleukodystrophy. METHODS: To establish the most frequent age and diagnostic neuroimaging modality for CCALD, we completed a meta-analysis of relevant studies published between January 1, 1970 and September 10, 2019. We used the consensus development conference method to incorporate the resulting data into guidelines to inform the timing and techniques for neuroimaging surveillance. Final guideline agreement was defined as >80% consensus. RESULTS: One hundred twenty-three studies met inclusion criteria yielding 1285 patients. The overall mean age of CCALD diagnosis is 7.91 years old. The median age of CCALD diagnosis calculated from individual patient data is 7.0 years old (IQR: 6.0-9.5, n = 349). Ninety percent of patients were diagnosed between 3 and 12. Conventional MRI was most frequently reported, comprised most often of T2-weighted and contrast-enhanced T1-weighted MRI. The expert panel achieved 95.7% consensus on the following surveillance parameters: (a) Obtain an MRI between 12 and 18 months old. (b) Obtain a second MRI 1 year after baseline. (c) Between 3 and 12 years old, obtain a contrast-enhanced MRI every 6 months. (d) After 12 years, obtain an annual MRI. CONCLUSION: Boys with adrenoleukodystrophy identified early in life should be monitored with serial brain MRIs during the period of highest risk for conversion to CCALD.
Assuntos
Adrenoleucodistrofia/diagnóstico , Imageamento por Ressonância Magnética , Criança , Pré-Escolar , Conferências de Consenso como Assunto , Humanos , Lactente , Recém-Nascido , Masculino , Triagem Neonatal/métodosRESUMO
The big island of Hawaii has been named the healing island - a place with varied interpretations of healing health, and a wide range of holistic health care practices. This research explores the perspectives of holistic providers about the communicative practices they believe are central to their interactions with patients. Intensive ethnographic interviews with 20 individuals revealed that they perceive their communication with clients as centered on four practices, specifically: (a) reciprocity - a mutual action or exchange in which both the practitioner and patient are equal partners in the healing process; (b) responsibility - the idea that, ultimately, people must heal themselves; (c) forgiveness - the notion that healing cannot progress if a person holds the burden of anger and pain; and (d) balance - the idea that it is possible to bring like and unlike things together in unity and harmony. The narratives revealed providers' ontological assumptions about mind-body systems and the rationalities they seek to resist in their conversations with patients.
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Atitude do Pessoal de Saúde , Terapias Complementares , Relações Metafísicas Mente-Corpo , Relações Profissional-Paciente , Espiritualidade , Antropologia Cultural , Feminino , Havaí , Saúde Holística , Humanos , Masculino , Narração , Havaiano Nativo ou Outro Ilhéu do Pacífico/psicologia , Terapias EspirituaisRESUMO
Bismuth telluride (Bi2Te3) nanowires were deposited into porous alumina templates with 35 nm diameter pores by a pulsed-potential electrodeposition method. For growth at temperatures between 1 and 4 degrees C, the nanowires filled 93% of the pores of the template, and the growth fronts were uniform with nanowire lengths of approximately 62-68 microm. There are over ten billion nanowires per square centimeter with aspect ratios approaching 2000:1. Samples were characterized by scanning and transmission electron microscopy, X-ray diffraction, and electron microprobe analysis. The crystalline nanowire arrays are highly oriented in the [110] direction, which is optimal for thermoelectric applications.