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1.
Paediatr Anaesth ; 29(10): 1053-1059, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31359511

RESUMO

BACKGROUND: Krabbe disease and metachromatic leukodystrophy are leukodystrophies characterized by neurologic degeneration and early death. Patients often require general anesthesia for diagnostic and therapeutic interventions. METHODS: A retrospective review of medical records was conducted for patients with Krabbe disease and metachromatic leukodystrophy receiving general anesthesia at a large children's hospital between 2012 and 2017. Patient complications and American Society of Anesthesiologists Physical Status were recorded for all procedures. The Neurodevelopment in Rare Disorders classification system was created to categorize the severity of the patient's disease progression based on clinical markers. Descriptive and inferential statistics were used to compare: (a) complication rate of affected patients vs the general hospital population; (b) the accuracy of the novel Neurodevelopment in Rare Disorders classification system vs American Society of Anesthesiologists Physical Status regarding the assessment of complication risk; (c) complication rate in patients with hematopoietic stem cell transplantation vs those without transplantation; (d) complication rate in immunosuppressed patients vs nonimmunosuppressed patients; and (e) complication rate of the three most commonly performed procedures. RESULTS: A total of 96 patients underwent 287 procedures. Of these, 11 cases had complications, yielding a rate of 3.8%. This is significantly higher than the overall complication rate at our institution of 0.246%. Statistical analysis showed better correlation between the Neurodevelopment in Rare Disorders classification system and complication rate than American Society of Anesthesiologists Physical Status and complication rate. The system also showed better accuracy in differentiating low-risk and high-risk patients. No statistically significant difference in complication rate was found for patients with transplantation vs those without transplantation or for immunosuppressed vs nonimmunosuppressed patients. Of the three most common procedures, central catheter placement/removal exhibited the highest complication rate. CONCLUSIONS: Although the complication rate for patients with Krabbe disease and metachromatic leukodystrophy is higher than the general population, most complications were mild and self-limiting. These results suggest that, in experienced hands, general anesthesia is well tolerated in most children. Findings show that the Neurodevelopment in Rare Disorders classification system is a better indicator for assessing complication risk in patients with Krabbe and metachromatic leukodystrophy than American Society of Anesthesiologists Physical Status.

2.
Orphanet J Rare Dis ; 14(1): 174, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300018

RESUMO

BACKGROUND: Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive neurodegenerative disorder with brain iron accumulation (NBIA). OBJECTIVES: To assess PKAN diagnostic pathway, history, and burden across the spectrum of PKAN severity from patient and/or caregiver perspectives. METHODS: Caregivers of patients (n = 37) and patients themselves (n = 2) were interviewed in a validation study of the PKAN-Activities of Daily Living (ADL) scale. The current study used quartiles of the PKAN-ADL total score to divide patients by severity of impairment (Lowest, Second Lowest, Third Lowest, Highest). Diagnostic and treatment history, healthcare utilization, disease burden, and caregiver experience were compared between groups. RESULTS: The analyses included data from 39 patients. Mean age at PKAN symptom onset (P = 0.0007), initial MRI (P = 0.0150), and genetic testing (P = 0.0016) generally decreased across the PKAN severity spectrum. The mean duration of illness did not differ among PKAN severity groups (range, 9.7-15.2 years; P = 0.3029). First MRI led to diagnosis in 56.4% of patients (range, 30.0-90.0%). A mean (SD) of 13.0 (13.1) medical and 55.2 (78.5) therapy visits (eg, physical, speech) occurred in the past year. More patients in the higher PKAN severity groups experienced multiple current functional losses and/or earlier onset of problems (P-values < 0.0500). Over half (56.8%) of caregivers experienced a change in employment because of caregiving. The percentage of patients requiring full-time caregiving increased across the PKAN severity spectrum (range, 11.1-100%; P = 0.0021). CONCLUSIONS: PKAN diagnosis was often delayed, most probably due to low awareness. Considerable burden of functional impairment and high healthcare utilization were found across the PKAN severity spectrum.

3.
Clin Trials ; 16(4): 410-418, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31055958

RESUMO

BACKGROUND/AIMS: Pantothenate kinase-associated neurodegeneration is a rare neurodegenerative disease with a variable clinical phenotype. Fosmetpantotenate is in clinical development as a replacement therapy that targets the underlying cause of pantothenate kinase-associated neurodegeneration. The FOsmetpantotenate Replacement Therapy pivotal trial-an ongoing phase 3, randomized, double-blind, placebo-controlled, multicenter trial-examines the efficacy and safety of fosmetpantotenate in patients with pantothenate kinase-associated neurodegeneration aged 6-65 years. The FOsmetpantotenate Replacement Therapy trial required the development and validation of a novel patient-reported outcome measure specifically relevant to pantothenate kinase-associated neurodegeneration. The Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living scale was developed to assess activities of daily living related to motor functioning in patients with pantothenate kinase-associated neurodegeneration to evaluate clinically meaningful change as the primary efficacy endpoint in clinical trials. This article describes the design of the FOsmetpantotenate Replacement Therapy pivotal trial and the development of the Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living scale. METHODS: A systematic, iterative process consistent with the US Food and Drug Administration guidance and advice from the Committee for Medicinal Products for Human Use at the European Medicines Agency was used to evaluate and adapt or remove scale items of an existing widely used instrument for movement disorders to be pantothenate kinase-associated neurodegeneration-specific, and to create new items. Modification of scale items was based on input from international experts, patient advocacy leaders, and primary caregivers. A clinimetric study of the Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living scale conducted in patients with pantothenate kinase-associated neurodegeneration or their caregivers (N = 40 at first assessment; N = 39 at second assessment) demonstrated high content and construct validity and excellent test-retest reliability over an approximately 2-week period. The Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living scale was developed to be broadly useful within clinical and research settings in the examination of patient response to pantothenate kinase-associated neurodegeneration therapies. RESULTS: Approximately 82 patients will be enrolled in the ongoing FOsmetpantotenate Replacement Therapy pivotal trial. Change from baseline in Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living score over the 24-week double-blind period is the primary efficacy endpoint for the FOsmetpantotenate Replacement Therapy trial. Treatment effect will be evaluated using a mixed model for repeated measures analysis to assess data from all visits simultaneously. CONCLUSION: The development and implementation of the Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living scale in the FOsmetpantotenate Replacement Therapy trial illustrates the feasibility and potential patient benefit of putting into practice the current regulatory guidance on the use of patient-reported outcomes in clinical trials. These processes can be broadly applied to clinical trial methodology that requires newly created or revised patient-reported outcome measures to evaluate outcome change as a primary efficacy endpoint. The goal of such measures in patients with pantothenate kinase-associated neurodegeneration is to facilitate development of disease-modifying therapeutics in multiple drug development programs.

4.
Orphanet J Rare Dis ; 14(1): 46, 2019 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-30777126

RESUMO

BACKGROUND: Krabbe disease is a rare neurological disorder caused by a deficiency in the lysosomal enzyme, ß-galactocerebrosidase, resulting in demyelination of the central and peripheral nervous systems. If left without treatment, Krabbe disease results in progressive neurodegeneration with reduced quality of life and early death. The purpose of this prospective study was to describe the natural progression of early onset Krabbe disease in a large cohort of patients. METHODS: Patients with early onset Krabbe disease were prospectively evaluated between 1999 and 2018. Data sources included diagnostic testing, parent questionnaires, standardized multidisciplinary neurodevelopmental assessments, and neuroradiological and neurophysiological tests. RESULTS: We evaluated 88 children with onset between 0 and 5 months. Median age of symptom onset was 4 months; median time to diagnosis after onset was 3 months. The most common initial symptoms were irritability, feeding difficulties, appendicular spasticity, and developmental delay. Other prevalent symptoms included axial hypotonia, abnormal deep tendon reflexes, constipation, abnormal pupillary response, scoliosis, loss of head control, and dysautonomia. Results of nerve conduction studies showed that 100% of patients developed peripheral neuropathy by 6 months of age. Median galactocerebrosidase enzyme activity was 0.05 nmol/h/mg protein. The median survival was 2 years. CONCLUSIONS: This is the largest prospective natural history study of Krabbe disease. It provides a comprehensive description of the disease during the first 2 years of life. With recent inclusion of state mandated newborn screening programs and promising therapeutic interventions, enhancing our understanding of disease progression in early onset Krabbe disease will be critical for developing treatments, designing clinical trials, and evaluating outcomes.


Assuntos
Leucodistrofia de Células Globoides/patologia , Triagem Neonatal/métodos , Criança , Progressão da Doença , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos
5.
Mol Genet Metab ; 126(2): 131-138, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30635159

RESUMO

Mucopolysaccharidosis IIIB is caused by a marked decrease in N-acetyl-α-d-glucosaminidase (NAGLU) enzyme activity, which leads to the accumulation of heparan sulfate in key organs, progressive brain atrophy, and neurocognitive decline. In this open-label study, 11 eligible patients aged 2 to <12 years (developmental age ≥ 1 year) were sequentially allocated to recombinant human NAGLU enzyme (SBC-103) in 3 staggered- and escalating-dose groups (0.3 mg/kg [n = 3], 1.0 mg/kg [n = 4], or 3.0 mg/kg [n = 4]) by intravenous infusion every 2 weeks for 24 weeks, followed by a 4-week interruption (Part A), treatment at 1.0 and/or 3.0 mg/kg every 2 weeks starting at week 28 (Part B), and treatment at 5.0 or 10.0 mg/kg every 2 weeks (Part C) for approximately 2 total years in the study. The primary objective of the study was safety and tolerability evaluation; secondary objectives included evaluation of SBC-103 effects on total heparan sulfate levels in cerebrospinal fluid (CSF), brain structural magnetic resonance imaging (cortical gray matter volume), and neurocognitive status (age equivalent/developmental quotient). During the study, 13 treatment-emergent serious adverse events (SAEs) occurred in 3 patients; 32 infusion-associated reactions (IARs) occurred in 8 patients. Most AEs were mild and intravenous treatment with SBC-103 was well tolerated. Mean (SD) changes from baseline at 52 weeks in Part C for the 5.0 and 10.0 mg/kg doses, respectively, were: -4.7% (8.3) and - 4.7% (14.7) for heparan sulfate levels in CSF, -8.1% (3.5) and - 10.3% (9.4) for cortical gray matter volume, +2.3 (6.9) points and +1.0 (9.2) points in cognitive age equivalent and -8.9 (10.2) points and -14.4 (9.2) points in developmental quotient. In summary, SBC-103 was generally well tolerated. Changes in heparan sulfate levels in CSF were small and were not maintained from earlier study time points, there was no clear evidence overall of clinically meaningful improvement in neurocognitive function at the higher doses investigated, and no dose-dependent effects were observed.


Assuntos
Acetilglucosaminidase/uso terapêutico , Mucopolissacaridose III/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Acetilglucosaminidase/administração & dosagem , Administração Intravenosa , Encéfalo , Criança , Pré-Escolar , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Heparitina Sulfato/líquido cefalorraquidiano , Humanos , Imagem por Ressonância Magnética , Masculino , Proteínas Recombinantes/administração & dosagem
6.
Genet Med ; 21(7): 1644-1651, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30546085

RESUMO

PURPOSE: Newborn screening for Krabbe disease (KD) originated in New York State in 2006 but has proven to have a high false positive rate and low positive predictive value. To improve accuracy of presymptomatic prediction, we propose a screening tool based on two biomarkers, psychosine and galactocerebrosidase enzyme activity (GalC). METHODS: We developed the tool using measures from dried blood spots of 166 normal newborns and tested it on dried blood spot measures from 15 newborns who later developed KD, 8 newborns identified as "high risk" by the New York screening protocol but were disease-free at follow-up, and 3 symptomatic children with onset before 4 years of age. The tool was developed from the (1-10-6)100% prediction region of the natural logarithms of psychosine and GalC measures, assuming bivariate normality, and their univariate normal limits. RESULTS: Krabbe disease was predicted correctly for every patient who developed symptoms in infancy or early childhood. None of the high-risk patients were incorrectly identified as having early KD. CONCLUSION: Bivariate analysis of psychosine and GalC in newborn blood spots can accurately predict early Krabbe symptoms, control false positive rates, and permit presymptomatic treatment.

7.
Artigo em Inglês | MEDLINE | ID: mdl-30292747

RESUMO

Cerebral adrenoleukodystrophy (CALD) is a rapidly progressing, often fatal neurodegenerative disease caused by mutations in the ABCD1 gene, resulting in deficiency of ALD protein. Clinical benefit has been reported following allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a large multicenter retrospective chart review to characterize the natural history of CALD, to describe outcomes after HSCT, and to identify predictors of treatment outcomes. Major functional disabilities (MFDs) were identified as having the most significant impact on patients' abilities to function independently and were used to assess HSCT outcome. Neurologic function score (NFS) and Loes magnetic resonance imaging score were assessed. Data were collected on 72 patients with CALD who did not undergo HSCT (untreated cohort) and on 65 patients who underwent transplantation (HSCT cohort) at 5 clinical sites. Kaplan-Meier (KM) estimates of 5-year overall survival (OS) from the time of CALD diagnosis were 55% (95% confidence interval [CI], 42.2% to 65.7%) for the untreated cohort and 78% (95% CI, 64% to 86.6%) for the HSCT cohort overall (P = .01). KM estimates of 2-year MFD-free survival for patients with gadolinium-enhanced lesions (GdE+) were 29% (95% CI, 11.7% to 48.2%) for untreated patients (n = 21). For patients who underwent HSCT with GdE+ at baseline, with an NFS ≤1 and Loes score of 0.5 to ≤9 (n = 27), the 2-year MFD-free survival was 84% (95% CI, 62.3% to 93.6%). Mortality rates post-HSCT were 8% (5 of 65) at 100 days and 18% (12 of 65) at 1 year, with disease progression (44%; 7 of 16) and infection (31%; 5 of 16) listed as the most common causes of death. Adverse events post-HSCT included infection (29%; 19 of 65), acute grade II-IV graft-versus-host disease (GVHD) (31%; 18 of 58), and chronic GVHD (7%; 4 of 58). Eighteen percent of the patients (12 of 65) experienced engraftment failure after their first HSCT. Positive predictors of OS in the HSCT cohort may include donor-recipient HLA matching and lack of GVHD, and early disease treatment was predictive of MFD-free survival. GdE+ status is a strong predictor of disease progression in untreated patients. This study confirms HSCT as an effective treatment for CALD when performed early. We propose survival without MFDs as a relevant treatment goal, rather than solely assessing OS as an indicator of treatment success.

8.
Orphanet J Rare Dis ; 13(1): 126, 2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-30089515

RESUMO

BACKGROUND: Krabbe disease is a rare neurodegenerative disorder caused by a deficiency in the lysosomal enzyme galactocerebrosidase. Patients with Krabbe disease present with a variable disease course depending on their age of onset. The purpose of this prospective cohort study was to characterize the natural progression of Krabbe disease in a large group of patients with disease onset between 6 and 36 months of life who were evaluated with a standardized protocol. METHODS: All patients with Krabbe disease who had onset between 6 and 36 months of age and were prospectively evaluated between 2000 to 2017 were included. Standardized neurodevelopmental, physical, and neurological examinations were performed. Other assessments included neuroradiologic and neurophysiologic tests, enzyme level, cerebrospinal fluid analysis, and GALC pathogenic variants when available. Descriptive statistics were used for analysis. Survival curve was estimated using the Kaplan-Meier method. RESULTS: Thirty-five patients (26 boys, 9 girls) with disease onset between 6 and 36 months of age were evaluated. Median age at symptom onset was 11.5 months, with a median delay of 3.5 months between onset of symptoms and diagnosis. Of the 32 symptomatic patients, 23 presented with initial signs or symptoms of disease between 6 and 12 months of life; nine presented after 12 months. The most common initial signs and symptoms were loss of acquired developmental milestones, irritability, abnormal gait, motor delay, and abnormal muscle tone. The most common magnetic resonance imaging abnormality was increased T2 signal in the periventricular white matter. Nerve conduction velocity results were abnormal for 21 of 24 patients. Patients with onset after 12 months had less peripheral nerve involvement and slower disease progression. Abnormal cerebrospinal fluid protein levels were obtained for 13 of 16 symptomatic children. Protein levels were normal in all asymptomatic children. CONCLUSIONS: Based on our findings, we propose reclassifying the group of patients with onset ≤12 months as infantile and the > 12 month group as late-infantile. Patients with onset > 12 months are more likely to benefit from hematopoietic stem cell transplantation. The proposed change in classifications will allow physicians to improve their ability to recognize and diagnose patients and more precisely assess potential treatment effects after transplantation.

9.
Mol Genet Metab ; 122S: 25-34, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29153844

RESUMO

The mucopolysaccharidosis (MPS) disorders are a group of lysosomal storage diseases caused by lysosomal enzyme deficits that lead to glycosaminoglycan accumulation, affecting various tissues throughout the body based on the specific enzyme deficiency. These disorders are characterized by their progressive nature and a variety of somatic manifestations and neurological symptoms. There are established treatments for some MPS disorders, but these mostly alleviate somatic and non-neurological symptoms and do not cure the disease. Patients with MPS I, II, III, and VII can present with neurological manifestations such as neurocognitive decline and behavioral problems. Treatment of these neurological manifestations remains challenging due to the blood-brain barrier (BBB) that limits delivery of therapeutic agents to the central nervous system (CNS). New therapies that circumvent this barrier and target brain disease in MPS are currently under development. They primarily focus on facilitating penetration of drugs through the BBB, delivery of recombinant enzyme to the brain by gene therapy, or direct CNS administration. This review summarizes existing and potential future treatment approaches that target brain disease in MPS. The information in this review is based on current literature and presentations and discussions during a closed meeting by an international group of experts with extensive experience in managing and treating MPS.


Assuntos
Encéfalo/efeitos dos fármacos , Disfunção Cognitiva/terapia , Terapia de Reposição de Enzimas/métodos , Mucopolissacaridoses/terapia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/citologia , Encéfalo/metabolismo , Criança , Comportamento Infantil/efeitos dos fármacos , Desenvolvimento Infantil/efeitos dos fármacos , Pré-Escolar , Ensaios Clínicos como Assunto , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Congressos como Assunto , Portadores de Fármacos/química , Terapia Genética/métodos , Glicosaminoglicanos/metabolismo , Glicosaminoglicanos/toxicidade , Transplante de Células-Tronco Hematopoéticas , Humanos , Injeções Intraventriculares , Injeções Espinhais , Chaperonas Moleculares/uso terapêutico , Mucopolissacaridoses/diagnóstico , Mucopolissacaridoses/genética , Mucopolissacaridoses/patologia , Nanopartículas/química , Proteínas Recombinantes/uso terapêutico
10.
Mol Genet Metab ; 122S: 8-16, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29128371

RESUMO

The mucopolysaccharidoses (MPS) are a group of rare, inherited lysosomal storage disorders in which accumulation of glycosaminoglycans (GAGs) leads to progressive tissue and organ dysfunction. In addition to a variety of somatic signs and symptoms, patients with rapidly progressing MPS I (Hurler), II, III, and VII can present with significant neurological manifestations, including impaired cognitive abilities, difficulties in language and speech, behavioral abnormalities, sleep problems, and/or seizures. Neurological symptoms have a substantial impact on the quality of life of MPS patients and their families. Due to the progressive nature of cognitive impairment in these MPS patients, neurocognitive function is a sensitive indicator of disease progression, and a relevant outcome when testing efficacy of therapies for these disorders. In order to effectively manage and develop therapies that address neurological manifestations of MPS, it is important to use appropriate neurocognitive assessment tools that are sensitive to changes in neurocognitive function in MPS patients. This review discusses expert opinions on key issues and considerations for effective neurocognitive testing in MPS patients. In addition, it describes the neurocognitive assessment tools that have been used in clinical practice for these patients. The content of this review is based on existing literature and information from a meeting of international experts with extensive experience in managing and treating MPS disorders.


Assuntos
Comportamento Infantil , Disfunção Cognitiva/diagnóstico , Glicosaminoglicanos/metabolismo , Mucopolissacaridoses/diagnóstico , Testes Neuropsicológicos/normas , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Criança , Desenvolvimento Infantil , Pré-Escolar , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Disfunção Cognitiva/terapia , Congressos como Assunto , Progressão da Doença , Glicosaminoglicanos/toxicidade , Humanos , Melatonina/farmacologia , Melatonina/uso terapêutico , Mucopolissacaridoses/genética , Mucopolissacaridoses/patologia , Mucopolissacaridoses/terapia , Neurologistas/psicologia , Neurologistas/normas , Pediatras/psicologia , Pediatras/normas , Relações Médico-Paciente , Guias de Prática Clínica como Assunto , Qualidade de Vida
11.
Mol Genet Metab ; 122S: 35-40, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29170079

RESUMO

The mucopolysaccharidosis (MPS) disorders are caused by deficiencies of specific lysosomal enzymes, resulting in progressive glycosaminoglycan (GAG) accumulation in cells and tissues throughout the body. Excessive GAG storage can lead to a variety of somatic manifestations as well as primary and secondary neurological symptoms. Behavioral problems (like hyperactivity, attention difficulties, and severe frustration) and sleeping problems are typical primary neurological symptoms of MPS caused by GAG accumulation in neurons, and are frequently observed in patients with MPS I, II, III, and VII. As these problems often place a significant burden on the family, proper management is important. This review summarizes current insights into behavioral and sleeping problems in MPS disorders and the most optimal management approaches, as presented and discussed during a meeting of an international group of experts with extensive experience in managing and treating MPS.


Assuntos
Terapia Comportamental/métodos , Depressores do Sistema Nervoso Central/uso terapêutico , Comportamento Infantil/efeitos dos fármacos , Dissonias/terapia , Mucopolissacaridoses/terapia , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Encéfalo/metabolismo , Depressores do Sistema Nervoso Central/farmacologia , Criança , Pré-Escolar , Congressos como Assunto , Dissonias/etiologia , Dissonias/psicologia , Glicosaminoglicanos/metabolismo , Glicosaminoglicanos/toxicidade , Humanos , Mucopolissacaridoses/complicações , Mucopolissacaridoses/patologia , Mucopolissacaridoses/psicologia , Resultado do Tratamento
12.
Mol Genet Metab ; 122S: 1-7, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29074036

RESUMO

The mucopolysaccharidoses (MPS) are a group of rare, inherited lysosomal storage disorders, caused by mutations in lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs). The resulting accumulation of GAGs in the body leads to widespread tissue and organ dysfunction. The spectrum, severity, and progression rate of clinical manifestations varies widely between and within the different MPS types. In addition to somatic signs and symptoms, which vary between the different MPS disorders, patients with MPS I, II, III, and VII present with significant neurological signs and symptoms, including impaired cognitive abilities, difficulties in language and speech, and/or behavioral and sleep problems. To effectively manage and develop therapies that target these neurological manifestations, it is of utmost importance to have a profound knowledge of their natural history and pathophysiology. This review describes the appearance and progression of neurological signs and symptoms in patients with MPS I, II, and III, based on presentations and discussions among an international group of experts during a meeting on the brain in MPS on April 28-30, 2016, and additional literature searches on this subject.


Assuntos
Encéfalo/crescimento & desenvolvimento , Disfunção Cognitiva/genética , Glicosaminoglicanos/toxicidade , Lisossomos/enzimologia , Mucopolissacaridoses/genética , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Criança , Comportamento Infantil/efeitos dos fármacos , Desenvolvimento Infantil/efeitos dos fármacos , Pré-Escolar , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/patologia , Disfunção Cognitiva/terapia , Congressos como Assunto , Progressão da Doença , Glicosaminoglicanos/metabolismo , Transplante de Células-Tronco Hematopoéticas , Humanos , Lisossomos/efeitos dos fármacos , Melatonina/farmacologia , Melatonina/uso terapêutico , Mucopolissacaridoses/diagnóstico , Mucopolissacaridoses/patologia , Mucopolissacaridoses/terapia , Testes Neuropsicológicos
13.
Mol Genet Metab ; 122(1-2): 18-32, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28863857

RESUMO

Leukodystrophies are a broad class of genetic disorders that result in disruption or destruction of central myelination. Although the mechanisms underlying these disorders are heterogeneous, there are many common symptoms that affect patients irrespective of the genetic diagnosis. The comfort and quality of life of these children is a primary goal that can complement efforts directed at curative therapies. Contained within this report is a systems-based approach to management of complications that result from leukodystrophies. We discuss the initial evaluation, identification of common medical issues, and management options to establish a comprehensive, standardized care approach. We will also address clinical topics relevant to select leukodystrophies, such as gallbladder pathology and adrenal insufficiency. The recommendations within this review rely on existing studies and consensus opinions and underscore the need for future research on evidence-based outcomes to better treat the manifestations of this unique set of genetic disorders.


Assuntos
Doenças Desmielinizantes/terapia , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/terapia , Leucoencefalopatias/terapia , Doenças por Armazenamento dos Lisossomos/prevenção & controle , Doenças por Armazenamento dos Lisossomos/terapia , Insuficiência Adrenal/terapia , Adulto , Criança , Doenças Desmielinizantes/congênito , Feminino , Vesícula Biliar/patologia , Predisposição Genética para Doença , Humanos , Leucoencefalopatias/congênito , Masculino , Qualidade de Vida
14.
Neurology ; 89(13): 1365-1372, 2017 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-28855403

RESUMO

OBJECTIVE: To describe long-term outcomes of children with early-infantile Krabbe disease who underwent hematopoietic stem cell transplantation (HSCT) in the first 7 weeks of life. METHODS: In this prospective longitudinal study, evaluations performed at baseline and follow-up included brain imaging, neurodiagnostic tests, and neurobehavioral evaluations. RESULTS: Of the 18 patients in this study (11 girls, 7 boys; mean follow-up 9.5 years, range 4-15), 5 died (3 of peritransplant complications, 1 of a surgical complication unrelated to Krabbe disease, 1 of disease progression). One of the surviving patients has normal cognitive function and 10 continue to develop cognitive skills at a slightly slower rate than normal. All surviving patients continue to gain receptive language skills, with 7 falling within the normal range. Ten patients receive speech therapy, and 2 of these patients require augmentative communication devices. Gross motor development varies widely, but 3 patients can walk independently, and 7 walk with assistive devices. Spasticity ranges from mild to severe, and 12 patients wear orthotics. Fine motor skills are generally preserved. Brain myelination and atrophy stabilized in 8 patients, improved in 4 patients, and worsened in 1 patient. Nerve conduction velocities initially improved but continue to be abnormal in most patients. CONCLUSIONS: The surviving patients function at a much higher level than untreated children or symptomatic children who underwent HSCT. These results show that early HSCT changes the natural history of this disease by improving both lifespan and functional abilities. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for children with early-infantile Krabbe disease, early HSCT improves lifespan and functional abilities.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Leucodistrofia de Células Globoides/fisiopatologia , Leucodistrofia de Células Globoides/terapia , Adolescente , Transplante de Medula Óssea , Encéfalo/diagnóstico por imagem , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiopatologia , Criança , Desenvolvimento Infantil , Pré-Escolar , Progressão da Doença , Feminino , Seguimentos , Humanos , Lactente , Estimativa de Kaplan-Meier , Leucodistrofia de Células Globoides/mortalidade , Leucodistrofia de Células Globoides/psicologia , Estudos Longitudinais , Masculino , Estudos Prospectivos , Resultado do Tratamento
15.
Clin Chem ; 63(8): 1363-1369, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28592445

RESUMO

BACKGROUND: Deficiency of the lysosomal enzyme galactosylcerebrosidase (GALC) causes Krabbe disease. Newborn screening for Krabbe disease is ongoing, but improved methods for follow-up analysis of screen-positive babies are needed to better advise families and to optimize treatment. We report a new assay for the enzymatic activity of GALC in lymphocytes. METHODS: T lymphocytes were isolated from venous blood by magnetic bead technology. The assay used a close structural analog of the natural substrate and LC-MS/MS to quantify the amount of product with the aid of a chemically identical internal standard. RESULTS: The analytical range of the assay (ratio of assay response for the QC high standard to that from all non-enzymatic-dependent processes) was 20-fold greater than that for the conventional radiometric GALC assay. The LC-MS/MS could distinguish cells that were null in GALC from those that contained traces of active enzyme (down to 0.3% of normal). There was a good correlation between the level of residual GALC activity in lymphocytes and the severity of Krabbe disease. CONCLUSIONS: The new assay can measure small amounts of residual GALC activity in leukocytes with high accuracy compared to previous assays and can contribute, along with genotyping, biomarker analysis, and neurological imaging, a better plan for post-newborn screening follow-up for Krabbe disease.


Assuntos
Galactosilceramidase/metabolismo , Leucodistrofia de Células Globoides/enzimologia , Triagem Neonatal/métodos , Linfócitos T/enzimologia , Criança , Cromatografia Líquida , Galactosilceramidase/análise , Galactosilceramidase/deficiência , Humanos , Recém-Nascido , Leucodistrofia de Células Globoides/metabolismo , Linfócitos T/metabolismo , Espectrometria de Massas em Tandem
16.
Mol Genet Metab ; 121(2): 70-79, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28501294

RESUMO

The design and conduct of clinical studies to evaluate the effects of novel therapies on central nervous system manifestations in children with neuronopathic mucopolysaccharidoses is challenging. Owing to the rarity of these disorders, multinational studies are often needed to recruit enough patients to provide meaningful data and statistical power. This can make the consistent collection of reliable data across study sites difficult. To address these challenges, an International MPS Consensus Conference for Cognitive Endpoints was convened to discuss approaches for evaluating cognitive and adaptive function in patients with mucopolysaccharidoses. The goal was to develop a consensus on best practice for the design and conduct of clinical studies investigating novel therapies for these conditions, with particular focus on the most appropriate outcome measures for cognitive function and adaptive behavior. The outcomes from the consensus panel discussion are reported here.


Assuntos
Cognição , Mucopolissacaridoses/terapia , Sistema Nervoso Central/fisiopatologia , Criança , Ensaios Clínicos como Assunto , Determinação de Ponto Final , Humanos , Mucopolissacaridoses/fisiopatologia , Mucopolissacaridose I/fisiopatologia , Mucopolissacaridose I/terapia , Mucopolissacaridose II/fisiopatologia , Mucopolissacaridose II/terapia , Mucopolissacaridose III/fisiopatologia , Mucopolissacaridose III/terapia , Doenças do Sistema Nervoso/terapia , Modalidades de Fisioterapia
17.
Orphanet J Rare Dis ; 12(1): 32, 2017 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-28193245

RESUMO

BACKGROUND: Newborn screening for mucopolysaccharidosis type I (MPS I) shows promise to improve outcomes by facilitating early diagnosis and treatment. However, diagnostic tests for MPS I are of limited value in predicting whether a child will develop severe central nervous system disease associated with Hurler syndrome, or minimal or no central nervous system involvement associated with the attenuated phenotypes (Hurler-Scheie and Scheie syndromes). Given that the optimal treatment differs between Hurler syndrome and the attenuated MPS I phenotypes, the absence of a reliable prognostic biomarker complicates clinical decision making for infants diagnosed through newborn screening. Information about the natural history of Hurler syndrome may aid in the management of affected infants, contribute to treatment decisions, and facilitate evaluation of treatment effectiveness and prognosis. Thus, the aim of this study was to characterize the progression and timing of symptom onset in infants with Hurler syndrome. RESULTS: Clinical data from 55 patients evaluated at a single center were retrospectively reviewed. Information about each child's medical history was obtained following a standardized protocol including a thorough parent interview and the review of previous medical records. All patients underwent systematic physical and neurodevelopmental evaluations by a multidisciplinary team. Nearly all patients (98%) showed signs of disease during the first 6 months of life. Common early disease manifestations included failed newborn hearing screen, respiratory symptoms, difficulty latching, and otitis media. Other symptoms such as kyphosis, corneal clouding, cardiac disease, joint restrictions, and enlarged head circumference typically appeared slightly later (median age, 8-10 months). During the first 12 months, gross motor development was the most severely affected area of functioning, and a significant number of patients also experienced language delays. Cognition was typically preserved during this period. CONCLUSIONS: In this large cohort of patients with Hurler syndrome, the vast majority showed signs and symptoms of disease during the first months of life. More research is needed to determine the extent to which early clinical manifestations of MPS I can predict phenotype and treatment outcomes.


Assuntos
Mucopolissacaridose I/patologia , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Recém-Nascido , Masculino , Mucopolissacaridose I/terapia , Estudos Retrospectivos
18.
Pediatr Blood Cancer ; 64(4)2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27873442

RESUMO

We describe the safety and feasibility of a forced deflation pulmonary function test (dPFT) in infants and young children. Fifty-two dPFT studies were performed in 26 patients (median age, 1.4 years). Forced vital capacity (FVC) and forced expiratory flow (FEF75 ) were normal in all except one case, but respiratory system compliance (Crs) was reduced in 24% patients. There were no significant differences in pre-blood and marrow transplantation FVC, FEF75 , and Crs between those patients who did and those who did not have posttransplant pulmonary complications. A larger study is needed to determine the prevalence and significance of PFT abnormalities in this age group.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Volume Expiratório Forçado/fisiologia , Pneumopatias/terapia , Testes de Função Respiratória/métodos , Insuficiência Respiratória/fisiopatologia , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Lactente , Masculino , Prognóstico , Insuficiência Respiratória/etiologia , Taxa de Sobrevida
19.
J Neurosci Res ; 94(11): 1118-25, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27638597

RESUMO

Krabbe disease (KD) is a rare neurodegenerative disorder caused by mutations in the gene encoding the galactocerebrosidase enzyme. The early- and late-infantile subtypes, which are the most common forms of the disease, are rapidly progressive and lead to early death, whereas the later-onset types are clinically heterogeneous. The only disease-modifying treatment currently available is hematopoietic stem cell transplantation, which is effective only when performed early in the course of the disease. Because most patients with KD are diagnosed too late for treatment, primary care physicians are faced with the challenge of caring for a child with severe neurologic impairment. This Review describes presenting symptoms, diagnosis, and disease manifestations of KD and provides basic guidelines for its management. Symptomatic treatment and supportive care that address the unique requirements of these patients can greatly improve the quality of life of patients and their families. © 2016 Wiley Periodicals, Inc.


Assuntos
Gerenciamento Clínico , Leucodistrofia de Células Globoides/diagnóstico , Leucodistrofia de Células Globoides/terapia , Guias como Assunto , Humanos
20.
Pediatr Endocrinol Rev ; 13 Suppl 1: 689-96, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27491217

RESUMO

Krabbe disease (globoid cell leukodystrophy, GLD) is an inherited disease caused by a deficiency in the lysosomal enzyme galactocerebrosidase (GALC). The major galactosylated lipid degraded by GALC is galactosylceramide. However, GALC is also responsible for the degradation of galactosylsphingosine (psychosine), a highly cytotoxic glycolipid. It has been hypothesized that GALC-deficiency leads to psychosine accumulation that preferentially kills oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. Krabbe disease has traditionally been considered a white matter disease characterized by the loss and disorganization of myelin, infiltration of multinucleated monocytes/macrophages (globoid cells) and lymphocytes, and dysregulation of pro-inflammatory cytokines and chemokines. However, new studies have revealed unexpected neuronal deficiencies. Infantile Krabbe disease is believed to be the most common and aggressive form. However, juvenile and adult onset forms have been described. Children affected with infantile Krabbe disease present with motor dysfunction, cognitive decline, intractable seizures, and premature death between two to five years of age. Murine, canine, and primate models of GALC deficiency have been described and have played an important role in our understanding of this invariably fatal disease. Although there is no cure for Krabbe disease, hematopoietic stem cell transplantation can slow the progression of disease. Recent pre-clinical data indicate that simulataneously targeting multiple pathogenic mechanisms greatly increases efficacy in the murine model of Krabbe disease. A better understanding of the underlying pathogenesis will identify new therapeutic targets that may further increase efficacy.


Assuntos
Transplante de Medula Óssea , Terapia de Reposição de Enzimas , Galactosilceramidase/uso terapêutico , Terapia Genética , Transplante de Células-Tronco Hematopoéticas , Leucodistrofia de Células Globoides/terapia , Acetilcisteína/uso terapêutico , Animais , Antimetabólitos/uso terapêutico , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Ciclosserina/uso terapêutico , Modelos Animais de Doenças , Depuradores de Radicais Livres/uso terapêutico , Galactosilceramidase/genética , Humanos , Leucodistrofia de Células Globoides/genética , Leucodistrofia de Células Globoides/fisiopatologia , Fenótipo , Inibidores de Fosfodiesterase/uso terapêutico , Piridinas/uso terapêutico
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