RESUMO
Our objective was to investigate brain structure, cerebral vasculature, and cognitive function in a cohort of patients with late-onset Pompe disease, with particular reference to the differences from those with the classic infantile phenotype, where extensive white-matter abnormalities (WMA) and impaired cognition on long-term enzyme treatment are reported in a subset of patients. Brain imaging (T1, T2, T2 fluid-attenuated inversion recovery, susceptibility-weighted images, and magnetic resonance angiography-time of flight) was combined with extensive cognitive testing of general intelligence (Wechsler IQ Test, Montreal Cognitive Assessment [MoCA]) and specific neuropsychological domains (verbal fluency, cognitive flexibility, attention, memory, and visuospatial abilities). We included 19 patients with late-onset Pompe disease (age range 11-56 years). Two patients showed mild punctate WMA within normal range for age, with a Fazekas score (FS) of 1 to 2. Magnetic resonance angiography revealed a slight vertebrobasilar dolichoectasia in two patients yet did not show any aneurysms or vascular dissections. Most patients had age-adjusted scores within the normal range for the Wechsler index scores (verbal comprehension, perceptual reasoning, working memory, and processing speed) and combined total intelligence (IQ) score (median 101, interquartile range 91-111; one patient had a below-average score for total IQ) as well as for the specific domains verbal fluency, attention, and memory. A subset of patients performed suboptimally on the Rey Complex Figure Test (9/14 patients) or cube-copying/clock-drawing test of the MoCA (8/10 patients). We therefore concluded that our study showed no brain abnormalities, other than minor microvascular lesions considered within normal range for age, nor general cognitive impairment in late-onset Pompe patients. These findings are in sharp contrast with the widespread WMA and cognitive problems found in some classic infantile patients.
Assuntos
Doença de Depósito de Glicogênio Tipo II , Encéfalo/patologia , Cognição , Doença de Depósito de Glicogênio Tipo II/patologia , Humanos , Testes de Inteligência , Imageamento por Ressonância Magnética , Testes NeuropsicológicosRESUMO
The aim of this study was to compare the long-term outcome of classic infantile Pompe patients treated with 20 mg/kg alglucosidase alfa every other week (eow) to those treated with 40 mg/kg/week, and to study the additional effect of immunomodulation. Six patients received 20 mg/kg eow and twelve 40 mg/kg/week. Five patients were cross-reactive immunologic material (CRIM)-negative, two in the 20 mg, three in the 40 mg group. We compared (ventilator-free) survival, motor outcome, infusion associated reactions (IARs), and antibody formation. From 2012 on patients >2 months in the 40 mg group also received immunomodulation with rituximab, methotrexate, and intravenous immunoglobulin (IVIG) in an enzyme replacement therapy (ERT)-naïve setting. Survival was 66% in the 20 mg group and 92% in the 40 mg group. Ventilator-free survival was 50% and 92%. Both CRIM-negative patients in the 20 mg group died, whereas all three are alive in the 40 mg group. In the 20 mg group, 67% learned to walk compared with 92% in the 40 mg group. At the age of 3 years, 33% and 92% were able to walk. Peak antibody titers ranged from 1:1250 to 1:31 250 in the 20 mg group and from 1:250 to 1:800 000 in the 40 mg group. Five patients of the 40 mg group of whom two CRIM-negative also received immunomodulation. B-cell recovery was observed between 5.7 and 7.9 months after the last dose of rituximab. After B-cell recovery titers of patients with and without immunomodulation were similar (ranges 1:6 250-1:800 000 and 1:250-1:781 250). This study shows that classic infantile patients treated with 40 mg/kg/week from the start to end have a better (ventilator-free) survival and motor outcome. Immunomodulation did not prevent antibody formation in our study.
Assuntos
Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , alfa-Glucosidases/uso terapêutico , Anticorpos/sangue , Criança , Pré-Escolar , Reações Cruzadas , Terapia de Reposição de Enzimas , Feminino , Doença de Depósito de Glicogênio Tipo II/imunologia , Humanos , Imunomodulação/efeitos dos fármacos , Lactente , Masculino , Estudos Prospectivos , Análise de Sobrevida , Resultado do Tratamento , alfa-Glucosidases/farmacologiaRESUMO
Enzyme replacement therapy has drastically changed prospects of patients with Pompe disease, a progressive metabolic myopathy. As classic infantile patients survive due to treatment, they exhibit progressive white matter abnormalities, while brain involvement in late-onset patients is not fully elucidated. To study the underlying microstructure of white matter, we acquired structural (T1, T2, FLAIR) and diffusion tensor imaging (DTI) of the brain in 12 classic infantile patients (age 5-20 years) and 18 late-onset Pompe patients (age 11-56 years). Structural images were scored according to a rating scale for classic infantile patients. Fractional anisotropy (FA) and mean diffusivity (MD) from classic infantile patients were compared to a reference population, using a Wilcoxon signed-rank, one sample test. Effect sizes (Hedges' G) were used to compare DTI metrics across different tracts. For late-onset patients, results were compared to (reported) tractography data on normal aging. In classic infantile patients, we found a significant lower FA and higher MD (p < 0.01) compared to the reference population. Large-association fibers were most severely affected. Classic infantile patients with advanced white matter abnormalities on structural MRI showed the largest deviations from the reference population. FA and MD were similar for younger and older late-onset patients in large WM-association fibers. We conclude that, while no deviations from typical neurodevelopment were found in late-onset patients, classic infantile Pompe patients showed quantifiable, substantially altered white matter microstructure, which corresponded with disease stage on structural MRI. DTI holds promise to monitor therapy response in future therapies targeting the brain.
Assuntos
Doença de Depósito de Glicogênio Tipo II , Substância Branca , Humanos , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Imagem de Tensor de Difusão/métodos , Doença de Depósito de Glicogênio Tipo II/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética/métodos , AnisotropiaRESUMO
BACKGROUND AND OBJECTIVES: Enzyme replacement therapy (ERT) has substantially improved the outcome of classic infantile Pompe disease, an inheritable muscle disease previously fatal at infancy. However, under treatment, patients develop white matter abnormalities and neurocognitive problems. Therefore, upcoming therapies also target the brain. Currently, biomarkers reflecting CNS involvement are lacking. We aimed to study the association of neurofilament light (NfL) and CNS involvement. METHODS: To investigate the potential of NfL, we analyzed serum samples of patients with classic infantile Pompe disease who were treated with ERT. The samples were collected at ages of <1, 5, and 10 years, as well as around MRI scans. We compared the outcomes with levels in age- and sex-matched peers. Control samples were originally collected as part of routine blood work in children who underwent small surgeries and stored in the biobank of the Erasmus MC/Sophia Children's Hospital. RESULTS: We analyzed 74 serum samples of 17 patients collected at ages ranging from 22 days to 21.2 years (1-8 samples per patient) and compared these with outcomes of 71 matched peers. In the first year of age, NfL levels in patients and controls were similar (10.3 vs 11.0 pg/mL), but mixed linear model analysis showed a yearly increase of NfL of 6.0% in patients, compared with a decrease of 8.8% in controls (p < 0.001). Higher NfL was associated with lower IQ scores (p = 0.009) and lower processing speed scores (p = 0.001). DISCUSSION: We found significant differences in NfL levels between patients and controls and a good association between NfL and cognition. NfL deserves further exploration as a biomarker for CNS involvement in patients with classic infantile Pompe disease.
Assuntos
Doença de Depósito de Glicogênio Tipo II , Criança , Humanos , Doença de Depósito de Glicogênio Tipo II/complicações , Filamentos Intermediários , Proteínas de Neurofilamentos , Encéfalo/diagnóstico por imagem , Cognição , BiomarcadoresRESUMO
BACKGROUND: Neonatal screening for Pompe disease is complicated by difficulties in predicting symptom onset in patients with the common c.-32-13T>G (IVS1) variant/null (i.e. fully deleterious) acid α-glucosidase (GAA) genotype. This splicing variant occurs in 90% of Caucasian late onset patients, and is associated with a broad range of symptom onset. METHODS: We analyzed a cohort of 143 compound heterozygous and 10 homozygous IVS1 patients, and we assessed ages at symptom onset, the presence of cis-acting single nucleotide variants (SNVs), and performed splicing analysis and enzyme activity assays. FINDINGS: In compound heterozygous IVS1 patients, the synonymous variant c.510C>T was uniquely present on the IVS1 allele in 9/33 (27%) patients with childhood onset, but was absent from 110 patients with onset in adulthood. GAA enzyme activity was lower in fibroblasts from patients who contained c.510C>T than it was in patients without c.510C>T. By reducing the extent of leaky wild-type splicing, c.510C>T modulated aberrant splicing caused by the IVS1 variant. The deleterious effect of c.510C>T was also found in muscle cells, the main target cells in Pompe disease. In homozygous IVS1 patients, the c.510C>T variant was absent in 4/4 (100%) asymptomatic individuals and present in 3/6 (50%) symptomatic patients. In cells from homozygous IVS1 patients, c.510C>T caused reduced leaky wild-type splicing. INTERPRETATION: c.510C>T is a genetic modifier in compound heterozygous and homozygous IVS1 patients. This finding is important for neonatal screening programs for Pompe disease. FUND: This work was funded by grants from Sophia Children's Hospital Foundation (SSWO, grant S17-32) and Metakids (2016-063).
Assuntos
Genes Modificadores , Estudos de Associação Genética , Predisposição Genética para Doença , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/genética , Fenótipo , Adolescente , Adulto , Idade de Início , Alelos , Criança , Pré-Escolar , Frequência do Gene , Genótipo , Doença de Depósito de Glicogênio Tipo II/metabolismo , Humanos , Lactente , Íntrons , Pessoa de Meia-Idade , Mutação , Splicing de RNA , Avaliação de Sintomas , Adulto Jovem , alfa-Glucosidases/genética , alfa-Glucosidases/metabolismoRESUMO
BACKGROUND: The antisaccade (AS) paradigm is frequently used to assess errors in reflexive behavioral responses in Parkinson's disease (PD) patients. Although PD pathology of frontal-striatal circuits suggests increased errors, reports on sensitivity and specificity of the AS task are lacking. We increased the level of cognitive complexity by adding to the AS task an antitapping instruction, i.e. an antisaccade and antitapping (ASAT) task. OBJECTIVE: In this study, we compared saccadic error rates between PD patients and age-matched controls in 1) an AS task, using only eye movements and 2) an ASAT task, using eye and hand movements. METHODS: 30 PD patients en 30 healthy age-matched controls performed an AS task and an ASAT task. The measurement setup consisted of a touch screen, an eye tracking system and a motion capture system. Error rates and eye - and hand latencies were compared between groups. RESULTS: PD patients show higher error rates in the ASAT task, but not in the AS task compared to controls. In correctly performed ASAT task trials, PD patients are on average 60 milliseconds faster to initiate an eye movement. Subject classification based on error rates and eye latencies in the ASAT task results in a sensitivity of 0.77 and a specificity of 0.63. CONCLUSIONS: The results suggest that saccadic error rates and eye latencies in the cognitively more demanding ASAT task are sensitive measures to differentiate PD patients from controls. This task is a potentially useful addition to current methods to investigate visuomotor deficits in PD.