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1.
Klin Padiatr ; 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32069498

RESUMO

Pompe disease is a rare metabolic myopathy caused by deficiency of lysosomal α-glucosidase. Reduced enzyme activity results in abnormal intra- and extralysosomal glycogen deposition as well as impaired cellular function and autophagy. Age at manifestation and severity of disease depend on residual enzyme activity. Enzyme replacement therapy (ERT) is available since 2006. In infantile onset Pompe disease, the most severe form, markedly prolonged survival has resulted in a new phenotype with symptoms and problems not encountered previously. In addition, it became apparent that antibody formation against the recombinant human enzyme may adversely affect the response to ERT. This review summarizes new knowledge gained in the last years concerning care of pediatric patients with Pompe disease and gives recommendations for diagnostics, treatment, and follow-up.

2.
JIMD Rep ; 49(1): 89-95, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31497486

RESUMO

Background: Early diagnosis is of substantial benefit for patients with Pompe disease. Yet underdiagnosing and substantial diagnostic delay are still frequent and the determinants of this are unknown. This study is the first to systematically investigate the diagnostic odyssey in Pompe disease from patients', parents', and physicians' perspectives. Methods: Patients with infantile or late onset Pompe disease, their parents as well as their metabolic experts were invited to fill in respective surveys. The survey addressed perceived disease symptoms at onset and during the course of the disease, specialties of involved physicians, activities of patient-initiated search for diagnosis and the perceived impact of time to diagnosis on outcome. Results of experts' and patients'/parents' surveys were compared and expressed by descriptive statistics. Results and Discussion: We collected data on 15 males and 17 females including 9 infantile and 23 late onset Pompe patients. All received the correct diagnosis at a metabolic or musculoskeletal expert center. Patients with direct referral to the expert center had the lowest diagnostic delay, while patients who were seen by several physicians, received the correct diagnosis after 44%-200% longer delay. The proportion of direct referral varied strongly between pediatricians (57%) and other disciplines (18%-36%). Conclusion: Our study highlights a substantially larger diagnostic delay in Pompe patients that are not directly referred to expert centers for diagnostic work. Our findings may be used to develop more successful strategies for early diagnosis. Synopsis: Diagnostic delay in Pompe disease is substantial particularly in patients that are not directly referred to expert centers for diagnostic workup, so facilitating direct referral may be a new strategy for early diagnosis.

3.
Clin Chim Acta ; 494: 58-63, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30876856

RESUMO

BACKGROUND: Niemann-Pick disease type C (NPC) is an autosomal recessive inherited disorder with progressive neuronal degeneration. Because conventional diagnostic methods are complicated and invasive, biomarker tests have drawn attention. We aimed to evaluate three urinary conjugated cholesterol metabolites as diagnostic biomarkers for NPC. METHODS: Urine samples from 23 patients with NPC, 28 healthy controls, and 7 patients with inherited metabolic disorders were analyzed. 3ß-Sulfooxy-7ß-N-acetylglucosaminyl-5-cholen-24-oic acid and its glycine and taurine conjugates in urine were quantified by liquid chromatography-tandem mass spectrometry. The diagnostic performance of the three metabolites and their total concentration was evaluated. RESULT: Creatinine-corrected concentrations of three metabolites and their total concentration were all significantly higher in NPC patients (0.0098 < P < .0448). The area under the receiver operating curve for all metabolites exceeded 0.95, the clinical specificity was 92-100%, and the clinical sensitivity was ~95%. In the urine of patients with other inherited metabolic diseases, the concentrations of the metabolites were lower than those in the urine of patients with NPC. CONCLUSION: These conjugated cholesterol metabolites in urine can serve as useful diagnostic markers for noninvasive screening of NPC.


Assuntos
Ésteres do Colesterol/urina , Doença de Niemann-Pick Tipo C/diagnóstico , Doença de Niemann-Pick Tipo C/urina , Adolescente , Adulto , Biomarcadores/metabolismo , Biomarcadores/urina , Criança , Pré-Escolar , Ésteres do Colesterol/metabolismo , Cromatografia Líquida , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Doença de Niemann-Pick Tipo C/metabolismo , Espectrometria de Massas em Tandem , Adulto Jovem
4.
Mol Genet Metab ; 126(2): 98-105, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30514648

RESUMO

BACKGROUND: Acid sphingomyelinase deficiency (ASMD), a rare lysosomal storage disease, results from mutations in SMPD1, the gene encoding acid sphingomyelinase (ASM). As a result, sphingomyelin accumulates in multiple organs including spleen, liver, lung, bone marrow, lymph nodes, and in the most severe form, in the CNS and peripheral nerves. Clinical manifestations range from rapidly progressive and fatal infantile neurovisceral disease, to less rapidly progressing chronic neurovisceral and visceral forms that are associated with significant morbidity and shorter life span due to respiratory or liver disease. OBJECTIVES: To provide a contemporary guide of clinical assessments for disease monitoring and symptom management across the spectrum of ASMD phenotypes. METHODS: An international group of ASMD experts in various research and clinical fields used an evidence-informed consensus process to identify optimal assessments, interventions, and lifestyle modifications. RESULTS: Clinical assessment strategies for major organ system involvement, including liver, spleen, cardiovascular, pulmonary, and neurological/developmental are described, as well as symptomatic treatments, interventions, and/or life style modifications that may lessen disease impact. CONCLUSIONS: There is currently no disease-specific treatment for ASMD, although enzyme replacement therapy with a recombinant human ASM (olipudase alfa) is in clinical development. Current monitoring addresses symptoms and multisystem involvement. Recommended interventions and lifestyle modifications are designed to address morbidity and disease complications and improve patient quality of life. While infantile neurovisceral ASMD is uniformly fatal in early childhood, patients with chronic visceral and chronic neurovisceral ASMD require appropriate management throughout childhood and adulthood by an interdisciplinary clinical team.


Assuntos
Gerenciamento Clínico , Monitorização Fisiológica/métodos , Doença de Niemann-Pick Tipo A/terapia , Guias de Prática Clínica como Assunto , Ensaios Clínicos como Assunto , Terapia de Reposição de Enzimas , Humanos , Monitorização Fisiológica/estatística & dados numéricos , Mutação , Doença de Niemann-Pick Tipo A/diagnóstico , Fenótipo , Qualidade de Vida , Comportamento de Redução do Risco
5.
Klin Padiatr ; 231(2): 52-59, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30481833

RESUMO

PURPOSE: We retrospectively assessed bone and visceral manifestations in patients with Gaucher disease type 1 (GD1) with whole-body magnetic resonance imaging (WB-MRI) to determine the effects of different timing in initiating long-term enzyme replacement therapy. MATERIALS AND METHODS: In 17 patients with GD1, we performed 2 WB-MRI examinations at a median interval of 13 months. Patients had received enzyme replacement therapy with alglucerase/imiglucerase for a median of 13 years prior to the first examination. MRI results were retrospectively stratified based on treatment initiation into 2 groups: "early" (age ≤12 years, median 5 years) and "late" (during adulthood, median 32 years). We evaluated occurrence of irreversible avascular necroses (AVN) and applied several semi-quantitative scores, including the Bone-Marrow-Burden (BMB) score, the Düsseldorf-Gaucher score (DGS), the Vertebra-Disc-Ratio (VDR), and the Gaucher disease type 1 Severity Scoring System (GD-DS3). RESULTS: MRI assessments showed no AVN in the "early" group. AVN were observed in 2 patients of the "late" group; one also had a splenic Gaucheroma. The follow-up examinations showed slight improvements in the BMB-score, DGS, and VDR, with similar tendencies in both treatment groups. The GD-DS3 score only improved in "late" group. CONCLUSION: This retrospective study supported the ongoing clinical value of enzyme replacement therapy with alglucerase/imiglucerase, as WB-MRI-based scores stayed constant or slightly improved even after long-term treatment. Secondary complications were only observed in the late treatment group. Our results suggest that "early initiation" of enzyme replacement therapy may protect the bone.


Assuntos
Terapia de Reposição de Enzimas/métodos , Doença de Gaucher/tratamento farmacológico , Glucosilceramidase/uso terapêutico , Imagem por Ressonância Magnética/métodos , Proteínas Recombinantes/uso terapêutico , Imagem Corporal Total , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Doença de Gaucher/diagnóstico , Humanos , Osteonecrose/induzido quimicamente , Osteonecrose/epidemiologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento
6.
Intern Med J ; 49(5): 578-591, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30414226

RESUMO

BACKGROUND: Gaucher disease (GD) presents with a range of signs and symptoms. Physicians can fail to recognise the early stages of GD owing to a lack of disease awareness, which can lead to significant diagnostic delays and sometimes irreversible but avoidable morbidities. AIM: The Gaucher Earlier Diagnosis Consensus (GED-C) initiative aimed to identify signs and co-variables considered most indicative of early type 1 and type 3 GD, to help non-specialists identify 'at-risk' patients who may benefit from diagnostic testing. METHODS: An anonymous, three-round Delphi consensus process was deployed among a global panel of 22 specialists in GD (median experience 17.5 years, collectively managing almost 3000 patients). The rounds entailed data gathering, then importance ranking and establishment of consensus, using 5-point Likert scales and scoring thresholds defined a priori. RESULTS: For type 1 disease, seven major signs (splenomegaly, thrombocytopenia, bone-related manifestations, anaemia, hyperferritinaemia, hepatomegaly and gammopathy) and two major co-variables (family history of GD and Ashkenazi-Jewish ancestry) were identified. For type 3 disease, nine major signs (splenomegaly, oculomotor disturbances, thrombocytopenia, epilepsy, anaemia, hepatomegaly, bone pain, motor disturbances and kyphosis) and one major co-variable (family history of GD) were identified. Lack of disease awareness, overlooking mild early signs and failure to consider GD as a diagnostic differential were considered major barriers to early diagnosis. CONCLUSION: The signs and co-variables identified in the GED-C initiative as potentially indicative of early GD will help to guide non-specialists and raise their index of suspicion in identifying patients potentially suitable for diagnostic testing for GD.


Assuntos
Consenso , Técnica Delfos , Doença de Gaucher/diagnóstico , Médicos/normas , Diagnóstico Precoce , Doença de Gaucher/fisiopatologia , Humanos
7.
World J Biol Psychiatry ; 20(4): 310-319, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-28914127

RESUMO

Objectives: Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease that should be recognised by psychiatrists as a possible underlying cause of psychiatric abnormalities. This study describes NP-C patients who had psychiatric manifestations at enrolment in the international NPC Registry, a unique multicentre, prospective, observational disease registry. Methods: Treating physicians' data entries describing psychiatric manifestations in NPC patients were coded and grouped by expert psychiatrists. Results: Out of 386 NP-C patients included in the registry as of October 2015, psychiatric abnormalities were reported to be present in 34% (94/280) of those with available data. Forty-four patients were confirmed to have identifiable psychiatric manifestations, with text describing these psychiatric manifestations. In these 44 patients, the median (range) age at onset of psychiatric manifestations was 17.9 years (2.5-67.9; n = 15), while the median (range) age at NP-C diagnosis was 23.7 years (0.2-69.8; n = 34). Almost all patients (43/44; 98%) had an occurrence of ≥1 neurological manifestation at enrolment. Conclusions: These data show that substantial delays in diagnosis of NP-C are long among patients with psychiatric symptoms and, moreover, patients presenting with psychiatric features and at least one of cognitive impairment, neurological manifestations, and/or visceral symptoms should be screened for NP-C.


Assuntos
Transtornos Mentais/diagnóstico , Doença de Niemann-Pick Tipo C/psicologia , Sistema de Registros , Adolescente , Adulto , Idade de Início , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Internacionalidade , Masculino , Transtornos Mentais/etiologia , Pessoa de Meia-Idade , Doença de Niemann-Pick Tipo C/complicações , Estudos Prospectivos , Adulto Jovem
8.
Orphanet J Rare Dis ; 13(1): 143, 2018 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-30115089

RESUMO

BACKGROUND: Niemann-Pick disease type C (NPC) is a lysosomal storage disease with a heterogeneous neurodegenerative clinical course. Multiple therapies are in clinical trials and inclusion criteria are currently mainly based on age and neurological signs, not taking into consideration differential individual rates of disease progression. RESULTS: In this study, we have evaluated a simple metric, denoted annual severity increment score (ASIS), that measures rate of disease progression and could easily be used in clinical practice. We show that ASIS is stable over several years and can be used to stratify patients for clinical trials. It achieves greater homogeneity of the study cohort relative to age-based inclusion and provides an evidence-based approach for establishing inclusion/exclusion criteria. In addition, we show that ASIS has prognostic value and demonstrate that treatment with an experimental therapy - acetyl-DL-leucine - is associated with a reduction in ASIS scores. CONCLUSION: ASIS has the potential to be a useful metric for clinical monitoring, trial recruitment, for prognosis and measuring response to therapy.


Assuntos
Leucina/análogos & derivados , Doença de Niemann-Pick Tipo C/diagnóstico , Doença de Niemann-Pick Tipo C/tratamento farmacológico , Adulto , Ensaios Clínicos como Assunto , Estudos de Coortes , Feminino , Humanos , Leucina/uso terapêutico , Doenças por Armazenamento dos Lisossomos/diagnóstico , Doenças por Armazenamento dos Lisossomos/tratamento farmacológico , Masculino , Inquéritos e Questionários , Adulto Jovem
9.
Orphanet J Rare Dis ; 13(1): 50, 2018 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-29625568

RESUMO

Niemann-Pick Type C (NPC) is a progressive and life limiting autosomal recessive disorder caused by mutations in either the NPC1 or NPC2 gene. Mutations in these genes are associated with abnormal endosomal-lysosomal trafficking, resulting in the accumulation of multiple tissue specific lipids in the lysosomes. The clinical spectrum of NPC disease ranges from a neonatal rapidly progressive fatal disorder to an adult-onset chronic neurodegenerative disease. The age of onset of the first (beyond 3 months of life) neurological symptom may predict the severity of the disease and determines life expectancy.NPC has an estimated incidence of ~ 1: 100,000 and the rarity of the disease translate into misdiagnosis, delayed diagnosis and barriers to good care. For these reasons, we have developed clinical guidelines that define standard of care for NPC patients, foster shared care arrangements between expert centres and family physicians, and empower patients. The information contained in these guidelines was obtained through a systematic review of the literature and the experiences of the authors in their care of patients with NPC. We adopted the Appraisal of Guidelines for Research & Evaluation (AGREE II) system as method of choice for the guideline development process. We made a series of conclusive statements and scored them according to level of evidence, strengths of recommendations and expert opinions. These guidelines can inform care providers, care funders, patients and their carers of best practice of care for patients with NPC. In addition, these guidelines have identified gaps in the knowledge that must be filled by future research. It is anticipated that the implementation of these guidelines will lead to a step change in the quality of care for patients with NPC irrespective of their geographical location.


Assuntos
Doença de Niemann-Pick Tipo C/terapia , Guias de Prática Clínica como Assunto , Humanos
10.
PLoS One ; 13(1): e0190784, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29315315

RESUMO

OBJECTIVE: The objective of this study was to evaluate a quantitative method based on conventional T1-weighted magnetic resonance (MR) imaging to assess fatty muscular degeneration in patients with late-onset Pompe disease and to compare it with semi-quantitative visual evaluation (the Mercuri score). In addition, a long-term retrospective data analysis was performed to evaluate treatment response to enzyme replacement therapy with alglucosidase alfa. METHODS: MR images of the lumbar spine were acquired in 41 patients diagnosed with late-onset Pompe disease from 2006 through 2015. Two independent readers retrospectively evaluated fatty degeneration of the psoas and paraspinal muscles by applying the Mercuri score. Quantitative semi-automated muscle and fat tissue separation was performed, and inter-observer agreement and correlations with clinical parameters were assessed. Follow-up examinations were performed in 13 patients treated with alglucosidase alfa after a median of 39 months; in 7/13 patients, an additional follow-up examination was completed after a median of 63 months. RESULTS: Inter-observer agreement was high. Measurements derived from the quantitative method correlated well with Medical Research Council scores of muscle strength, with moderate correlations found for the 6-minute walk test, the 4-step stair climb test, and spirometry in the supine position. A significant increase in the MR-derived fat fraction of the psoas muscle was found between baseline and follow-up 1 (P = 0.016), as was a significant decrease in the performance on the 6-minute walk test (P = 0.006) and 4-step stair climb test (P = 0.034), as well as plasma creatine kinase (P = 0.016). No statistically significant difference in clinical or MR-derived parameters was found between follow-up 1 and follow-up 2. CONCLUSIONS: Quantification of fatty muscle degeneration using the semi-automated method can provide a more detailed overview of disease progression than semi-quantitative Mercuri scoring. MR-derived data correlated with clinical symptoms and patient exercise capacity. After an initial worsening, the fat fraction of the psoas muscle and performance on the 6-minute walk test stayed constant during long-term follow-up under enzyme replacement therapy.


Assuntos
Tecido Adiposo/diagnóstico por imagem , Terapia de Reposição de Enzimas/métodos , Doença de Depósito de Glicogênio Tipo II/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Músculo Esquelético/diagnóstico por imagem , alfa-Glucosidases/administração & dosagem , Adolescente , Adulto , Idade de Início , Idoso , Criança , Feminino , Seguimentos , Doença de Depósito de Glicogênio Tipo II/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Variações Dependentes do Observador , Estudos Retrospectivos , Adulto Jovem
11.
Orphanet J Rare Dis ; 12(1): 144, 2017 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-28838325

RESUMO

BACKGROUND: Late-onset Pompe disease is a rare genetic neuromuscular disorder caused by lysosomal acid alpha-glucosidase (GAA) deficiency that ultimately results in mobility loss and respiratory failure. Current enzyme replacement therapy with recombinant human (rh)GAA has demonstrated efficacy in subjects with late-onset Pompe disease. However, long-term effects of rhGAA on pulmonary function have not been observed, likely related to inefficient delivery of rhGAA to skeletal muscle lysosomes and associated deficits in the central nervous system. To address this limitation, reveglucosidase alfa, a novel insulin-like growth factor 2 (IGF2)-tagged GAA analogue with improved lysosomal uptake, was developed. This study evaluated the pharmacokinetics, safety, and exploratory efficacy of reveglucosidase alfa in 22 subjects with late-onset Pompe disease who were previously untreated with rhGAA. RESULTS: Reveglucosidase alfa plasma concentrations increased linearly with dose, and the elimination half-life was <1.2 h. Eighteen of 22 subjects completed 72 weeks of treatment. The most common adverse events were hypoglycemia (63%), dizziness, fall, headache, and nausea (55% for each). Serious adverse events included hypersensitivity (n = 1), symptomatic hypoglycemia (n = 2), presyncope (n = 1), and acute cardiac failure (n = 1). In the dose-escalation study, all treated subjects tested positive for anti-reveglucosidase alfa, anti-rhGAA, anti-IGF1, and anti-IGF2 antibodies at least once. Subjects receiving 20 mg/kg of reveglucosidase alfa demonstrated increases in predicted maximum inspiratory pressure (13.9%), predicted maximum expiratory pressure (8.0%), forced vital capacity (-0.4%), maximum voluntary ventilation (7.4 L/min), and mean absolute walking distance (22.3 m on the 6-min walk test) at 72 weeks. CONCLUSIONS: Additional studies are needed to further assess the safety and efficacy of this approach. Improvements in respiratory muscle strength, lung function, and walking endurance in subjects with LOPD may make up for the risk of hypersensitivity reactions and hypoglycemia. Reveglucosidase alfa may provide a new treatment option for patients with late-onset Pompe disease. TRIAL REGISTRATION: ISRCTN01435772 and ISRCTN01230801 , registered 27 October 2011.


Assuntos
Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , alfa-Glucosidases/efeitos adversos , alfa-Glucosidases/uso terapêutico , Adulto , Terapia de Reposição de Enzimas/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo
12.
Mol Genet Metab ; 122(3): 122-129, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28847676

RESUMO

Gaucher disease (GD) is a rare hereditary disorder caused by a deficiency of the lysosomal enzyme ß-glucocerebrosidase. Diagnosis is challenging owing to a wide variability in clinical manifestations and severity of symptoms. Many patients may experience marked delays in obtaining a definitive diagnosis. The two surveys reported herein aimed to explore the patient journey to diagnosis of GD from the perspectives of Gaucher expert physicians and patients. Findings from the surveys revealed that many patients experienced diagnostic delays and misdiagnoses, with nearly 1 in 6 patients stating that they were not diagnosed with GD for 7years or more after first consulting a doctor. Physicians and patients both reported multiple referrals to different specialties before a diagnosis of GD was obtained, with primary care, haematology/haematology-oncology and paediatrics the main specialties to which patients first presented. Splenomegaly, thrombocytopenia, anaemia and bone pain were reported as the most common medical problems at first presentation in both surveys. These findings support a clear need for straightforward and easy-to-follow guidance designed to assist non-specialists to identify earlier patients who are at risk of GD.


Assuntos
Doença de Gaucher/diagnóstico , Pacientes/psicologia , Médicos/psicologia , Criança , Diagnóstico Tardio , Humanos , Masculino , Medicina/estatística & dados numéricos , Fatores de Risco , Inquéritos e Questionários
13.
Front Neurol ; 8: 711, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29379464

RESUMO

Objectives: To evaluate the function of the oculomotor and vestibular systems and to correlate these findings with the clinical status of patients with Gaucher disease type 3 (GD3). The goal of this cross-sectional and longitudinal study was to find oculomotor biomarkers for future clinical trials. Methods: Twenty-six patients with GD3 were assessed for eligibility and 21 were able to perform at least one task. Horizontal and vertical reflexive saccades, smooth pursuit, gaze-holding, optokinetic nystagmus, and horizontal vestibulo-ocular reflex (VOR) were examined by video-oculography/video-head impulse test and compared concurrently with 33 healthy controls. The Scale for the Assessment and Rating of Ataxia (SARA), the modified Severity Scoring Tool (mSST), and Grooved Pegboard Test (GPT) were administered to assess overall neurological function. Eleven patients were also re-assessed after 1 year. Results: Nine out of 17 patients exhibited gaze-holding deficits. One patient had upbeat nystagmus. Three patients presented with bilateral abducens palsy in combination with central oculomotor disorders, suggesting a bilateral involvement of the abducens nucleus. Horizontal angular VOR gain was reduced in all patients (0.66 ± 0.37) compared with controls (1.1 ± 0.11, p < 0.001). Most strongly correlated with clinical rating scales were peak velocity of downward saccades (SARA: ρ = -0.752, p < 0.0005; mSST: ρ = -0.611, p = 0.003; GPT: ρ = -0.649, p = 0.005) and duration of vertical saccades (SARA: ρ = 0.806, p < 0.001; mSST: ρ = 0.700, p < 0.0005; GPT: ρ = 0.558, p = 0.02) together with the VOR gain (SARA: ρ = -0.63, p = 0.016; mSST: ρ = -0.725, p = 0.003; GPT: ρ = -0.666, p = 0.004). Vertical smooth pursuit gain decreased significantly at follow-up. Interpretation: This study shows neuronal degeneration of the brainstem and cerebellum with combined involvement of both supranuclear and nuclear oculomotor structures and the vestibular system in GD3. We also identified oculomotor parameters that correlate with the neurological status and can be used as biomarkers in future clinical trials.

14.
JIMD Rep ; 33: 33-39, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27450368

RESUMO

Several different lysosomal storage diseases, mainly mucopolysaccharidosis (MPS) type I, II, and VI, are complicated by severe obstruction of the upper airways, tracheobronchial malacia, and/or stenosis of the lower airways. Although enzyme replacement therapies (ERTs) are available, the impact of these on tracheobronchial alterations has not been reported. By extending the life expectancy of MPS patients with ERTs, airway problems may become more prevalent at advanced ages. These airway abnormalities can result in severe, potentially fatal, difficulties during anesthetic procedures. Usually, upper airway obstruction is treated by tracheostomy. However, with lower airway malacia and/or stenosis, there are no procedures available to date to address these difficulties. We report the first cases using a new technique of tracheal stenting in patients with MPS type VI (Maroteaux-Lamy syndrome) and type II (Hunter syndrome) who had almost complete tracheal occlusion and total airway collapse. An updated literature review is also reported.

15.
Mol Genet Metab ; 120(3): 180-189, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27993458

RESUMO

BACKGROUND: Niemann-Pick disease Type C (NP-C) is a genetic lipid storage disorder characterised by progressive neurovisceral symptomatology. Typically, disease progression is more pronounced in patients with early onset of neurological symptoms. Heterogeneous clinical presentation may hinder disease recognition and lead to delays in diagnosis. Here we describe the prevalence of signs and symptoms observed in patients with NP-C and analyse the relationship between these symptoms in different age groups. METHODS: The combined patient cohort used in the analyses comprised NP-C cases (n=164) and controls (n=135) aged 0 to 60years from two previously published cohorts; a cohort of all ages from which patients ≤4years of age were excluded and a cohort with early-onset NP-C and age-matched controls. The analysis of relationships between different signs and symptoms was performed for both NP-C cases and controls in two sub-groups, ≤4 and >4years of age, using cluster analyses. The threshold of 4years of age was selected to reflect the minimum age cut-off for satisfactory discriminatory power of the original NP-C SI. To assess the prevalence of individual signs and symptoms at age of diagnosis, patients were categorised by age into 5-year sub-groups, and prevalence values estimated for each sign and symptom of NP-C. RESULTS: Two main clusters of symptoms were clearly defined for NP-C cases in each age sub-group, whereas clusters were not as clearly defined for controls. For NP-C cases ≤4years of age, one cluster comprised exclusively visceral symptoms; the second cluster combined all other signs and symptoms in this age group. For NP-C cases >4years of age, each cluster contained a mixture of visceral, neurological and psychiatric items. Prevalence estimations showed that visceral symptoms (e.g. isolated unexplained splenomegaly) were most common in NP-C cases ≤4years of age. Neurological symptoms were generally more common in NP-C cases >4years of age than in younger patients, with the exception of hypotonia and delayed developmental milestones. CONCLUSIONS: These analyses provide a comprehensive overview of symptomatology observed in a large combined cohort of patients with NP-C and controls across a wide range of ages. The results largely reflect observations from clinical practice and support the importance of multi-disciplinary approaches for identification of patients with NP-C, taking into account age-specific manifestations and their possible correlations.


Assuntos
Transtornos Mentais/epidemiologia , Doenças do Sistema Nervoso/epidemiologia , Doença de Niemann-Pick Tipo C/patologia , Esplenomegalia/epidemiologia , Vísceras/patologia , Adolescente , Adulto , Fatores Etários , Idade de Início , Criança , Pré-Escolar , Análise por Conglomerados , Progressão da Doença , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Doença de Niemann-Pick Tipo C/complicações , Prevalência , Adulto Jovem
16.
Mol Genet Metab ; 120(1-2): 62-66, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27876313

RESUMO

The differential diagnoses for metabolic liver diseases may be challenging in clinical settings, which represents a critical issue for disorders such as lysosomal acid lipase deficiency (LAL-D). LAL-D is caused by deficient activity of the LAL enzyme, resulting in the accumulation of cholesteryl esters and triglycerides throughout the body, predominately in the liver, spleen, gastrointestinal tract, and blood vessel walls. LAL-D is a progressive, multi-organ disease with early mortality and significant morbidity characterized by a combination of hepatic dysfunction and dyslipidemia. Evidence suggests LAL-D may be substantially underdiagnosed or misdiagnosed, which is critical given that disease progression can be unpredictable, with liver failure and/or accelerated atherosclerosis potentially contributing to early mortality. However, given the development of a simple diagnostic test and recently approved treatment, LAL-D should be incorporated into the differential diagnosis in relevant clinical settings. LAL-D can be diagnosed using an LAL enzyme-based biochemical test, thereby allowing for active monitoring of patients to detect potential disease complications and consider treatment options including diet, lipid-lowering medication, and treatment with sebelipase alfa, a recombinant enzyme replacement therapy shown to provide clinical benefit and improve disease-relevant markers in clinical trials. To illustrate the complexity of diagnosing LAL-D, this manuscript will describe the path to diagnosing LAL-D in a series of patient cases in which LAL-D was diagnosed as well as in patients where other diseases, such as Gaucher disease and Niemann-Pick disease, were initially suspected.


Assuntos
Esterol Esterase/metabolismo , Esterol Esterase/uso terapêutico , Doença de Wolman/diagnóstico , Doença de Wolman/tratamento farmacológico , Adolescente , Criança , Ésteres do Colesterol/metabolismo , Diagnóstico Diferencial , Progressão da Doença , Diagnóstico Precoce , Feminino , Doença de Gaucher/metabolismo , Humanos , Lactente , Masculino , Doenças de Niemann-Pick/metabolismo , Triglicerídeos/metabolismo , Doença de Wolman/metabolismo
17.
Neuromuscul Disord ; 27(2): 141-152, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27927596

RESUMO

The effects of enzyme replacement therapy (ERT) in infantile Pompe disease are variable, necessitating the identification of biomarkers to assess the severity of disease and response to ERT. The aims of this study were to investigate whether quantification of muscle pathology in infantile Pompe disease prior to and during ERT is feasible at the light microscope, and to develop a score that summarizes the degree of muscle pathology in a comprehensive manner from PAS-stained resin sections alone. We, therefore, determined glycogen load, extent of muscle fibre disruption, and amount of autophagic vacuoles in resin-embedded muscle biopsy specimens from 11 infantile Pompe patients and 2 with early childhood phenotype by quantitative methods, correlated the findings with ultrastructural analyses, compared PAS-stained resin sections with conventional PAS-stained cryosections, and related the quantified degree of muscle damage from infantile patients to the effects of ERT. Comparison of electron and light microscopic findings demonstrated that important alterations of skeletal muscle morphology can also be depicted by examining PAS stained resin sections. Infantile patients with good response to ERT had lower muscle pathology score values prior to and during ERT than those with moderate and poor response, but the number of tissue samples available for evaluation was limited. These findings suggest that quantification of muscle pathology by analysing PAS stained resin sections is in principle feasible and useful to monitor disease progression and therapy response. These results have to be validated by investigating a larger group of patients.


Assuntos
Doença de Depósito de Glicogênio Tipo II/patologia , Músculo Esquelético/patologia , Índice de Gravidade de Doença , alfa-Glucosidases/farmacologia , Idade de Início , Criança , Pré-Escolar , Terapia de Reposição de Enzimas , Feminino , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Humanos , Lactente , Masculino , Músculo Esquelético/ultraestrutura , alfa-Glucosidases/administração & dosagem
18.
Am J Med Genet A ; 173(2): 375-383, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27774754

RESUMO

Efficacy and safety of elosulfase alfa enzyme replacement therapy (ERT) were assessed in an open-label, phase 2, multi-national study in Morquio A patients aged ≥5 years unable to walk ≥30 meters in the 6-min walk test. Patients received elosulfase alfa 2.0 mg/kg/week intravenously for 48 weeks. Efficacy measures were functional dexterity, pinch/grip strength, mobility in a modified timed 25-foot walk, pain, quality of life, respiratory function, and urine keratan sulfate (KS). Safety/tolerability was also assessed. Fifteen patients received elosulfase alfa, three patients discontinued ERT due to adverse events (two were grade 3 drug-related adverse events, the other was not drug-related), and two patients missed >20% of planned infusions; 10 completed treatment through 48 weeks and received ≥80% of planned infusions (Modified Per Protocol [MPP] population). The study population had more advanced disease than that enrolled in other trials. From baseline to week 48, MPP data showed biochemical efficacy (urine KS decreased 52.4%). The remaining efficacy results were highly variable due to challenges in test execution because of severe skeletal and joint abnormalities, small sample sizes, and clinical heterogeneity among patients. Eight patients showed improvements in one or more outcome measures; several patients indicated improvements not captured by the study assessments (e.g., increased energy, functional ability). The nature of adverse events was similar to other elosulfase alfa studies. This study illustrates the considerable challenges in objectively measuring impact of ERT in very disabled Morquio A patients and highlights the need to examine results on an individual basis. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.


Assuntos
Condroitina Sulfatases/uso terapêutico , Terapia de Reposição de Enzimas , Mucopolissacaridose IV/diagnóstico , Mucopolissacaridose IV/tratamento farmacológico , Caminhada , Atividades Cotidianas , Adolescente , Adulto , Biomarcadores , Criança , Condroitina Sulfatases/administração & dosagem , Condroitina Sulfatases/efeitos adversos , Exercício , Feminino , Humanos , Sulfato de Ceratano/urina , Masculino , Qualidade de Vida , Testes de Função Respiratória , Autorrelato , Resultado do Tratamento , Adulto Jovem
19.
J Inherit Metab Dis ; 39(6): 831-837, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27590017

RESUMO

Current treatment options for MPS I have limited effects on some organs, including the skeletal system. In MPS animal models pentosan polysulphate (PPS) reduces the concentrations of glycosaminoglycans (GAGs) in tissues and body fluids and improves cartilaginous and osseous pathologies. The goals of this study were to investigate primarily the safety and secondary the clinical effects, concerning mobility and pain, of PPS treatment in MPS I patients. Four MPS I-Hurler-Scheie/-Scheie patients aged 35.6 ± 6.4 years with one male were included in the study. All patients were on enzyme replacement therapy since 9.45 ± 3.75 years. PPS was applied subcutaneously in two patients with 1 mg/kg and in two patients with 2 mg/kg, weekly for 12 weeks and then biweekly for 12 weeks. The 24-week treatment with PPS was well tolerated by all patients. Urinary GAG concentrations were reduced from 4.13 ± 1.17 at baseline to 2.69 ± 0.36 mg/mmol creatinine after 24-week treatment with 1 mg/kg PPS, and from 6.71 ± 0.62 to 2.65 ± 0.09 mg/mmol creatinine with 2 mg/kg PPS. An improvement in range of motion was noted in three out of four patients. The pain intensity score was reduced from 4.5 ± 1.77 at baseline to 1.8 ± 0.47 after 24-week treatment with 1 mg/kg PPS; patients with 2 mg/kg PPS already had minimal pain at the start of the study. In conclusion, PPS treatment in a small number of adult MPS I patients was well tolerated and resulted in a significant reduction of urinary GAG excretion and in an improvement of joint mobility and pain.


Assuntos
Mucopolissacaridose I/tratamento farmacológico , Poliéster Sulfúrico de Pentosana/uso terapêutico , Adulto , Animais , Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Terapia de Reposição de Enzimas/métodos , Feminino , Glicosaminoglicanos/metabolismo , Humanos , Masculino , Mucopolissacaridose I/metabolismo , Amplitude de Movimento Articular/efeitos dos fármacos
20.
PLoS One ; 11(9): e0162612, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27610627

RESUMO

BACKGROUND: Mucopolysaccharidosis (MPS) IVA is a rare lysosomal storage disorder with multiple skeletal and non-skeletal abnormalities requiring multiple surgical interventions. It is well known that patients with MPS IVA suffer from tachycardia, but cardiac and hemodynamic alterations have not been reported to date. We investigated the cardiovascular and hemodynamic alterations in patients with MPS IVA and developed a possible patho-mechanism for cardiovascular deterioration during anesthesia. MATERIAL AND METHODS: In this observational study, serial cardiac examinations were performed in 54 patients with MPS IVA who were followed at the Children's Hospital of the Mainz Medical University (Mainz, Germany) between 1991 and 2014 (follow-up 1-24 years; median 5.8 years). Results were compared with data from a large central European cohort of more than 2000 healthy infants and children. RESULTS: None of the patients had arterial hypertension, but 4% had evidence of increased pulmonary artery pressure. Patients developed aortic root extension up to 6.9 standard deviations above normal. Left-sided valve leaflet thickening occurred in 26 patients (five with valve disease). Patients had lower left ventricular dimensions (z: -1.02±0.1), lower stroke volumes (z: -2.3±0.17), lower left ventricular mass (z: -1.5±0.21), but higher wall thickness (z: +0.8±0.16), and higher work index (z: +2.5±0.2) compared to healthy control subjects. Cardiac output was preserved by an increase in heart rate of 21%. Sixty % of patients showed impaired diastolic filling; heart rate (99.0±1.8 vs. 92.0±2.1 bpm), age (18.0±1.8 vs. 14.2±1 years), and cardiothoracic ratio (61.6±3.6% vs. 55±4.2%) of these patients were higher compared to those with normal filling. CONCLUSIONS: The results of this study suggest an age-progressive disproportion of the intra-thoracic organs of patients with MPS IVA, which is accompanied by aortic root extension and thickened left ventricles, with reduced stroke volumes, impaired diastolic filling patterns, and increased heart rates.


Assuntos
Sistema Cardiovascular/fisiopatologia , Coração/fisiologia , Coração/fisiopatologia , Mucopolissacaridose IV/fisiopatologia , Adolescente , Pressão Sanguínea/fisiologia , Débito Cardíaco/fisiologia , Criança , Feminino , Frequência Cardíaca/fisiologia , Ventrículos do Coração/fisiopatologia , Hemodinâmica/fisiologia , Humanos , Hipertensão Pulmonar/fisiopatologia , Masculino , Estudos Observacionais como Assunto , Artéria Pulmonar/fisiopatologia , Adulto Jovem
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