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1.
Clin Neurophysiol Pract ; 9: 94-101, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38440119

RESUMO

Objective: Vincristine, a widely used anticancer chemotherapy drug, may cause polyneuropathy (PNP), potentially resulting in permanent functional impairment. We characterized the occurrence and development of vincristine-induced neuropathy (VIPN) in early treatment of childhood leukemia. Methods: This prospective study of 35 pediatric acute lymphoblastic leukemia (ALL) patients comprised systematic clinical and electrophysiological studies at both the time of diagnosis and at least one time point during the first months of treatment. Results: After vincristine treatment, all patients had axonal sensorimotor PNP on electroneuromyography (ENMG) In 34/35 patients, the motor and in 24/35 the sensory responses were decreased. Interestingly, in 3 patients PNP was most prominent in the upper limb. However, some children had no PNP symptoms despite moderate ENMG findings, and not all clinical symptoms were correlated with abnormal ENMG. Conclusions: Pediatric VIPN is a sensorimotor, predominantly motor axonal neuropathy. VIPN can be detected even in its early phase by ENMG, but it is difficult to detect by symptoms and clinical examination only. Significance: Pediatric ALL patients treated with vincristine are at risk of developing VIPN. Since the clinical signs of PNP in acutely ill children are difficult to identify, VIPN can easily be overlooked if ENMG is not performed.

2.
Neuro Oncol ; 26(2): 362-373, 2024 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-37758202

RESUMO

BACKGROUND: Studies have established that radiotherapy for childhood brain tumors (BTs) increases the risk of cerebrovascular disease (CVD); however, it is unclear how this will affect cognitive function. This study aimed to investigate the associations between radiotherapy-induced CVD, white matter hyperintensities (WMHs), and neurocognitive outcomes in adult survivors of childhood BTs. METHODS: In a cross-sectional setting, we conducted a national cohort that included 68 radiotherapy-treated survivors of childhood BTs after a median follow-up of 20 years. Markers of CVD and WMHs were evaluated using brain MRI, and the sum of CVD-related findings was calculated. Additionally, the associations among CVD findings, WMHs, and neuropsychological test results were analyzed. RESULTS: Of the 68 childhood BT survivors, 54 (79%) were diagnosed with CVD and/or WMHs at a median age of 27 years. CVD and/or WMHs were associated with lower scores for verbal intelligence quotient, performance intelligence quotient (PIQ), executive function, memory, and visuospatial ability (P < .05). Additionally, survivors with microbleeds had greater impairments in the PIQ, processing speed, executive function, and visuospatial ability (P < .05). WMHs and CVD burden were associated with greater difficulties in memory function and visuospatial ability (P < .05). Small-vessel disease burden was associated with PIQ scores, processing speed, working memory, and visuospatial ability. CONCLUSIONS: The study results suggest that markers of radiotherapy-induced CVD, the additive effect of CVD markers, and risk factors of dementia are associated with cognitive impairment, which may suggest that the survivors are at a high risk of developing early-onset dementia.


Assuntos
Neoplasias Encefálicas , Doenças Cardiovasculares , Disfunção Cognitiva , Demência , Humanos , Adulto , Encéfalo/patologia , Estudos Transversais , Testes Neuropsicológicos , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Imageamento por Ressonância Magnética , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/patologia , Demência/patologia , Doenças Cardiovasculares/patologia
3.
Pediatr Res ; 95(1): 102-111, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37563452

RESUMO

BACKGROUND: The aim of the study was to characterize molecular diagnoses in patients with childhood-onset progressive neurological disorders of suspected genetic etiology. METHODS: We studied 48 probands (age range from newborn to 17 years old) with progressive neurological disorders of unknown etiology from the largest pediatric neurology clinic in Finland. Phenotypes included encephalopathy (54%), neuromuscular disorders (33%), movement disorders (11%), and one patient (2%) with hemiplegic migraine. All patients underwent whole-exome sequencing and disease-causing genes were analyzed. RESULTS: We found 20 (42%) of the patients to have variants in genes previously associated with disease. Of these, 12 were previously reported disease-causing variants, whereas eight patients had a novel variant on a disease-causing gene: ATP7A, CHD2, PURA, PYCR2, SLC1A4, SPAST, TRIT1, and UPF3B. Genetics also enabled us to define atypical clinical presentations of Rett syndrome (MECP2) and Menkes disease (ATP7A). Except for one deletion, all findings were single-nucleotide variants (missense 72%, truncating 22%, splice-site 6%). Nearly half of the variants were de novo. CONCLUSIONS: The most common cause of childhood encephalopathies are de novo variants. Whole-exome sequencing, even singleton, proved to be an efficient tool to gain specific diagnoses and in finding de novo variants in a clinically heterogeneous group of childhood encephalopathies. IMPACT: Whole-exome sequencing is useful in heterogeneous pediatric neurology cohorts. Our article provides further evidence for and novel variants in several genes. De novo variants are an important cause of childhood encephalopathies.


Assuntos
Encefalopatias , Doenças do Sistema Nervoso , Neurologia , Síndrome de Rett , Recém-Nascido , Humanos , Criança , Adolescente , Doenças do Sistema Nervoso/genética , Fenótipo , Espastina/genética , Proteínas de Ligação a RNA/genética
5.
BMC Musculoskelet Disord ; 24(1): 441, 2023 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-37259117

RESUMO

BACKGROUND: Childhood brain tumor (BT) survivors have an increased risk of treatment-related late effects, which can reduce health-related quality of life and increase morbidity. This study aimed to investigate lumbar disc degeneration in magnetic resonance imaging (MRI) in adult survivors of radiotherapy-treated childhood BT compared to age and sex-matched population controls. METHODS: In this cross-sectional comparative study, 127 survivors were identified from hospital registries. After a mean follow-up of 20.7 years (range 5-33.1), 67 survivors (mean age 28.4, range 16.2-43.5) were investigated with MRI and compared to 75 sex-matched population-based controls. Evaluated MRI phenotypes included Pfirrmann grading, , intervertebral disc protrusions, extrusions, and high-intensity-zone-lesions (HIZ). Groups were also compared for known risk factors of lumbar intervertebral disc (IVD) degeneration. RESULTS: Childhood BT survivors had higher Pfirrmann grades than controls at all lumbar levels (all p < 0.001). Lumbar disc protrusions at L4-5 (p = 0.02) and extrusions at L3-4 (p = 0.04), L4-5 (p = 0.004), and L5-S1 (p = 0.01) were significantly more common in the BT group compared to the control. The survivor cohort also had significantly more HIZ-lesons than the controls (n=13 and n=1, p=0.003). Age at diagnosis was associated with lower degree of IVD degeneration (p < 0.01). Blood pressure correlated with IVD degeneration (P < 0.05). CONCLUSIONS: Signs of early disc degeneration related to tumor treatment can be seen in the IVDs of survivors. Disc degeneration was more severe in children treated in adolescence.


Assuntos
Neoplasias Encefálicas , Degeneração do Disco Intervertebral , Deslocamento do Disco Intervertebral , Disco Intervertebral , Criança , Humanos , Degeneração do Disco Intervertebral/patologia , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/patologia , Estudos Transversais , Qualidade de Vida , Deslocamento do Disco Intervertebral/complicações , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/complicações , Imageamento por Ressonância Magnética/métodos , Disco Intervertebral/patologia
6.
PLoS One ; 17(9): e0274274, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36067205

RESUMO

PURPOSE: Growth failure is common in radiotherapy-treated long-term survivors of pediatric brain tumors, but studies on longitudinal growth in this patient group are lacking. Here, the aim was to assess the changes in growth patterns before and after brain tumor diagnosis, the adult height, and the risk factors for compromised growth. The incidence and treatment practices of growth hormone deficiency were analyzed. METHODS: A cohort of 73 survivors of childhood brain tumor (median age 27.2 years, range 16.2 to 43.8 years) was studied after a median follow-up period of 20.4 years from diagnosis (IQR 14.9 to 22.9 years). Patients were treated in five university hospitals in Finland between 1970 and 2008. Growth curves, final height, and patient- and disease-related risk factors for compromised growth during different growth periods were analyzed. Laboratory analyses for IGF-1 and IGFBP-3 were performed at the follow-up. RESULTS: Growth failure was evident at diagnosis, with a mean height decline of -0.6 SDS (standard deviation score) from birth (95% CI -1.15 to -0.05). Mean height SDS decline after the diagnosis was -1.09 SDS (95%CI -1.51 to -0.66). At follow-up, 37% of the study subjects (27/73) had true short stature (height < -2 SDS). The mean height deficit corrected for target height was -1.9 SDS (95% CI -1.45 to -2.40). Growth failure was associated with the age at diagnosis, corticosteroid dose, radiotherapy modality and mean dose of irradiation in the thalamic area. Low IGF-1 level (below -2.0 SDS) was found in 32% (23/72), and untreated growth hormone deficiency in 40% (29/72) of the subjects. CONCLUSION: Longitudinal growth impairment was common in radiotherapy-treated survivors of childhood brain tumor, resulting in compromised adult height. Loss of growth potential was evident already at diagnosis and further accelerated by the treatments. At young adulthood, unrecognized growth hormone deficiency was common.


Assuntos
Neoplasias Encefálicas , Hormônio do Crescimento Humano , Adolescente , Adulto , Estatura , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Criança , Insuficiência de Crescimento/tratamento farmacológico , Hormônio do Crescimento , Humanos , Fator de Crescimento Insulin-Like I/análise , Sobreviventes , Adulto Jovem
7.
Int J Pediatr Otorhinolaryngol ; 156: 111099, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35276528

RESUMO

OBJECTIVES: Cytomegalovirus (CMV) is the most common congenital infection affecting about 0.6% of all newborns in developed countries. Vertical transmission to fetus can take place either after maternal primary or non-primary CMV infection during pregnancy. It is the most common infectious agent for sensorineural hearing loss (SNHL) in young children. The hearing loss after congenital CMV (cCMV) may be present at birth, or may develop after months or even years. In this study, we evaluated hearing outcome at 3-4 years of age in children (n 32) with cCMV identified in universal saliva CMV-PCR-based screening. METHODS: Study population consisted of mainly asymptomatic children (median age 3.1 years) with cCMV identified in newborn CMV screening. The type of maternal CMV infection (primary or non-primary) was determined by analyzing CMV antibodies (IgM, IgG and IgG avidity) from preserved maternal serum samples drawn in the end of first trimester of pregnancy. Hearing was evaluated with pure tone audiometry (PTA), or transient-evoked otoacoustic emission (TEOAE) and sound field audiometry (SF). RESULTS: Unilateral hearing loss occurred in 5/32 (16%) of the children with cCMV. None of the subjects in our cohort had bilateral hearing loss. Hearing loss occurred in 3/15 (20%) of children who were born to mothers with non-primary CMV infection during pregnancy, and in 2/10 (20%) of children whose mother had had a primary CMV infection during the 2-3 trimester. None of the additional 6 children, whose mother had primary infection in the first trimester, had hearing loss by age of 3-4 years. Two children with normal hearing at 1 years age had developed unilateral hearing loss by the age of three. CONCLUSIONS: Unilateral hearing loss was relatively common among the mainly asymptomatic children with cCMV identified in screening. Long-term follow up of children with cCMV is essential to identify the children with late-onset hearing loss.


Assuntos
Infecções por Citomegalovirus , Surdez , Perda Auditiva Neurossensorial , Perda Auditiva Unilateral , Audiometria de Tons Puros , Criança , Pré-Escolar , Citomegalovirus , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/epidemiologia , Feminino , Finlândia/epidemiologia , Seguimentos , Audição , Perda Auditiva Neurossensorial/congênito , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/epidemiologia , Humanos , Imunoglobulina G , Lactente , Recém-Nascido , Gravidez
8.
Support Care Cancer ; 30(6): 5157-5166, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35243538

RESUMO

PURPOSE: Survivors of childhood brain tumors (BT) are at high risk for long-term physical and psychological sequelae. Still, knowledge about health-related quality of life (HRQL) and associated factors in this population is sparse. This study investigated HRQL and its predictors in long-term survivors of childhood BT. METHODS: Survivors of childhood BT (mean age = 28.1 years, SD = 6.8, n = 60) underwent clinical examination and neurocognitive examination, and completed self-rating questionnaires assessing HRQL (RAND-36) and depressive symptoms (Beck Depression Inventory-II). Socio-demographic information was gathered via a questionnaire. Tumor- and treatment-related information was collected from medical records. Control group data were collected from age-matched controls (n = 146) without a history of cancer, randomly selected from the local population registry. Multiple linear regression models were used to investigate predictors of HRQL; separate models were fitted for each domain of the RAND-36. RESULTS: Male survivors (mean age = 27.0, SD = 6.0, n = 39) reported significantly lower HRQL than male controls in the domains of physical functioning, general health, vitality, social functioning, and role limitations-emotional. Female survivors (mean age = 30.2 years, SD = 7.6, n = 21) reported comparable levels as female controls in all domains except physical functioning. A higher burden of late effects, not working/studying, being diagnosed with BT during adolescence, and reporting current depressive symptoms were significant predictors of lower HRQL. CONCLUSION: Our results highlight that male survivors of childhood BT are at particular risk of impaired HRQL. Also, results point to the close relation between symptoms of depression and impaired HRQL in survivors of childhood BT which should be acknowledged by long-term follow-up care.


Assuntos
Neoplasias Encefálicas , Qualidade de Vida , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Qualidade de Vida/psicologia , Inquéritos e Questionários , Sobreviventes
9.
Eur J Paediatr Neurol ; 37: 1-7, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34999443

RESUMO

Deleterious variants in the transcription factor early B-cell factor 3 (EBF3) are known to cause a neurodevelopmental disorder (EBF3-NDD). We report eleven individuals with EBF3 variants, including an individual with a duplication/triplication mosaicism of a region encompassing EBF3 and a phenotype consistent with EBF3-NDD, which may reflect the importance of EBF3 gene-dosage for neurodevelopment. The phenotype of individuals in this cohort was quite mild compared to the core phenotype of previously described individuals. Although ataxia tended to wane with age, we show that cognitive difficulties may increase, and we recommend that individuals with EBF3-NDD have systematic neuropsychological follow-up.


Assuntos
Mosaicismo , Transtornos do Neurodesenvolvimento , Fatores de Transcrição , Ataxia/genética , Dosagem de Genes , Humanos , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Fatores de Transcrição/genética
10.
Eur J Paediatr Neurol ; 36: 30-36, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34852981

RESUMO

OBJECTIVES: To clarify the diagnostic utility and the cost-effectiveness of whole-exome sequencing (WES) as a routine early-diagnostic tool in children with progressive neurological disorders. METHODS: Patients with infantile-onset severe neurological diseases or childhood-onset progressive neurological disorders were prospectively recruited to this WES study, in the pediatric neurology clinic at Helsinki University Hospital during 2016-2018. A total of 48 patients underwent a singleton WES. A control group of 49 children underwent traditional diagnostic examinations and were retrospectively collected from the hospital records. Their use of health care services, related to the diagnostic process, was gathered. Incremental cost-effectiveness ratio (ICER) per additional diagnosis was calculated from the health care provider perspective. Bootstrapping methods were used to estimate the uncertainty of cost-effectiveness outcomes. RESULTS: WES provided a better diagnostic yield (38%) than diagnostic pathway that did not prioritize WES in early diagnosis (25%). WES outperformed other diagnostic paths especially when made early, within one year of first admission (44%). Cost-effectiveness in our results are conservative, affected by WES costs during 2016-18. CONCLUSIONS: WES is an efficient and cost-effective diagnostic tool that should be prioritized in early diagnostic path of children with progressive neurological disorders. The progressively decreasing price of the test improves cost-effectiveness further.


Assuntos
Testes Genéticos , Doenças do Sistema Nervoso , Criança , Análise Custo-Benefício , Humanos , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/genética , Estudos Retrospectivos , Sequenciamento do Exoma
11.
Neurooncol Pract ; 8(3): 266-277, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34055374

RESUMO

BACKGROUND: Little is known of the cognitive functions, employment, and social status in adult survivors of childhood brain tumor (BT). We aimed to determine the long-term neurocognitive profile of radiotherapy-treated adult survivors of childhood BT and the relationship between cognitive functions and employment and social status. METHODS: Neurocognitive profiles of survivors were assessed in a Finnish national cohort of 71 radiotherapy-treated survivors of childhood BT (median follow-up time: 21 years [range: 5-33 years]) using a cross-sectional design. Neurocognitive outcomes were compared to control (n = 45) and normative values. Tumor- and treatment-related data were collected from the patient files. Information on employment and social status was gathered. RESULTS: Survivors' (median age: 27 years [range: 16-43 years]) median verbal and performance intelligence quotient (IQ) was 90 (range: 49-121) and 87 (range: 43-119), respectively. The cognitive domains with the greatest impairment were executive functions (median z score, -3.5 SD [range: -25.0 to 1.3 SD]), and processing speed and attention (median z score, -2.5 SD [range: -24.9 to 0.5 SD]). Executive functions were associated with employment, educational level, living independently, having an intimate relationship, and having a driving license. Processing speed and attention were related to educational level, living independently, having an intimate relationship, and having a driving license. Performance IQ was associated with educational level and employment status. Working memory was associated with educational level and living independently. CONCLUSIONS: Radiotherapy-treated adult survivors of childhood BT experience significant neurocognitive impairment, which is associated with difficulties related to employment and social status.

12.
Acta Paediatr ; 110(3): 881-888, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32794225

RESUMO

AIM: The aim was to compare the performances of the World Health Organization (WHO) and population-based (PB) references in the screening for hydrocephalus in infants aged <2 years. METHODS: We collected 341 longitudinal head circumference (HC) measurements of hydrocephalic infants and 120 181 measurements of 15 145 healthy infants from primary care. The measurements were converted into z-scores, and a new screening parameter, change in HC standard deviation score (SDS) over time (ΔHC SDS), was calculated. Comparisons were made using receiver operating characteristics analysis and linear mixed models. RESULTS: The mean HC SDSWHO was 3.5 and the mean HC SDSPB was 2.9 in the hydrocephalic infants, and in healthy children, those numbers were 1.0 SDSWHO and 0 SDSPB , respectively. The best screening accuracy was obtained with the PB reference in combination with the ΔHC SDS parameter (AUC 0.89). The accuracy of the WHO standard could be improved to a similar level by customising the screening cut-offs of HC SDS according to the population and combining screening parameters. CONCLUSIONS: Auxology alone was not sufficient for the screening of hydrocephalus. The WHO standard should be validated in the population, and population-specific cut-offs for normality defined before its introduction.


Assuntos
Hidrocefalia , Idoso , Cefalometria , Criança , Cabeça/anatomia & histologia , Humanos , Hidrocefalia/diagnóstico , Lactente , Programas de Rastreamento , Organização Mundial da Saúde
13.
J Inherit Metab Dis ; 44(2): 469-480, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32857451

RESUMO

The aim of this study was to compare the value of serum biomarkers, fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), with histological analysis of muscle in the diagnosis of mitochondrial disease. We collected 194 serum samples from patients with a suspected or known mitochondrial disease. Biomarkers were analyzed blinded using enzyme-labeled immunosorbent assay. Clinical data were collected using a structured questionnaire. Only 39% of patients with genetically verified mitochondrial disease had mitochondrial pathology in their muscle histology. In contrast, biomarkers were elevated in 62% of patients with genetically verified mitochondrial disease. Those with both biomarkers elevated had a muscle manifesting disorder and a defect affecting mitochondrial DNA expression. If at least one of the biomarkers was induced and the patient had a myopathic disease, a mitochondrial DNA expression disease was the cause with 94% probability. Among patients with biomarker analysis and muscle biopsy taken <12 months apart, a mitochondrial disorder would have been identified in 70% with analysis of FGF21 and GDF15 compared to 50% of patients whom could have been identified with muscle biopsy alone. Muscle findings were nondiagnostic in 72% (children) and 45% (adults). Induction of FGF21 and GDF15 suggest a mitochondrial etiology as an underlying cause of a muscle manifesting disease. Normal biomarker values do not, however, rule out a mitochondrial disorder, especially if the disease does not manifest in muscle. We suggest that FGF21 and GDF15 together should be first-line diagnostic investigations in mitochondrial disease complementing muscle biopsy.


Assuntos
DNA Mitocondrial/genética , Fatores de Crescimento de Fibroblastos/genética , Fator 15 de Diferenciação de Crescimento/genética , Doenças Mitocondriais/genética , Adolescente , Adulto , Biomarcadores/sangue , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/sangue , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Adulto Jovem
14.
Neurooncol Pract ; 7(4): 415-427, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32760593

RESUMO

BACKGROUND: Cranial radiotherapy may damage the cerebral vasculature. The aim of this study was to understand the prevalence and risk factors of cerebrovascular disease (CVD) and white matter hyperintensities (WMHs) in childhood brain tumors (CBT) survivors treated with radiotherapy. METHODS: Seventy CBT survivors who received radiotherapy were enrolled in a cross-sectional study at a median 20 years after radiotherapy cessation. The prevalence of and risk factors for CVD were investigated using MRI, MRA, and laboratory testing. Tumors, their treatment, and stroke-related data were retrieved from patients' files. RESULTS: Forty-four individuals (63%) had CVD at a median age of 27 years (range, 16-43 years). The prevalence rates at 20 years for CVD, small-vessel disease, and large-vessel disease were 52%, 38%, and 16%, respectively. Ischemic infarcts were diagnosed in 6 survivors, and cerebral hemorrhage in 2. Lacunar infarcts were present in 7, periventricular or deep WMHs in 34 (49%), and mineralizing microangiopathy in 21 (30%) survivors. Multiple pathologies were detected in 44% of the participants, and most lesions were located in a high-dose radiation area. Higher blood pressure was associated with CVD and a presence of WMHs. Higher cholesterol levels increased the risk of ischemic infarcts and WMHs, and lower levels of high-density lipoprotein and higher waist circumference increased the risk of lacunar infarcts. CONCLUSIONS: Treating CBTs with radiotherapy increases the risk of early CVD and WMHs in young adult survivors. These results suggest an urgent need for investigating CVD prevention in CBT patients.

15.
Neurol Genet ; 6(4): e444, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32637629

RESUMO

OBJECTIVE: To characterize the genetic background of molecularly undefined childhood-onset ataxias in Finland. METHODS: This study examined a cohort of patients from 50 families with onset of an ataxia syndrome before the age of 5 years collected from a single tertiary center, drawing on the advantages offered by next generation sequencing. A genome-wide genotyping array (Illumina Infinium Global Screening Array MD-24 v.2.0) was used to search for copy number variation undetectable by exome sequencing. RESULTS: Exome sequencing led to a molecular diagnosis for 20 probands (40%). In the 23 patients examined with a genome-wide genotyping array, 2 additional diagnoses were made. A considerable proportion of probands with a molecular diagnosis had de novo pathogenic variants (45%). In addition, the study identified a de novo variant in a gene not previously linked to ataxia: MED23. Patients in the cohort had medically actionable findings. CONCLUSIONS: There is a high heterogeneity of causative mutations in this cohort despite the defined age at onset, phenotypical overlap between patients, the founder effect, and genetic isolation in the Finnish population. The findings reflect the heterogeneous genetic background of ataxia seen worldwide and the substantial contribution of de novo variants underlying childhood ataxia.

16.
J Community Genet ; 11(4): 461-473, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32248430

RESUMO

This study examines how parents of pediatric patients might differ in their views and attitudes towards genetic technology and information when compared to adult patients. There is surprisingly little evidence on how parents compare to other parts of population in their attitudes. Previous empirical studies often relate health-related preferences and attitudes to factors such as age, education, and income instead of parental status, thus evading comparison of parents to others as health-related decision makers. Findings related to the parental status can be useful when implementing genetic technology in clinical practice. We conducted a survey of views on genetic technology and information for groups of adult neurology patients (n = 68) and parents of pediatric neurology patients (n = 31) to shed some light on this issue. In addition to our own survey instrument, we conducted other surveys to gain insight on psychosocial factors that might affect these attitudes. The results suggest that parents are more concerned about their children's genetic risk factors when compared to the attitudes of adult patients about their own risk. For both groups, negative emotional state was associated with more concerns towards genetic information. Our study provides insights on how parental views might affect the acceptance of genetic technology and information.

17.
J Clin Virol ; 125: 104287, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32086150

RESUMO

BACKGROUND: Children with congenital CMV infection (cCMV) shed virus in urine and saliva for prolonged periods of time. Outcome of cCMV varies from asymptomatic infection with no sequelae in most cases, to severe longterm morbidity. The factors associated with asymptomatic cCMV are not well defined. We evaluated the viral shedding in a cohort of infants with cCMV identified on newborn screening. In addition, we describe the distribution of viral genotypes in our cohort of asymptomatic infants and previous cohorts of cCMV children in the literature. METHODS: Study population consisted of 40 children with cCMV identified in screening of 19,868 infants, a prevalence of 2/1000. The viral shedding was evaluated at 3 and 18 months of age by real-time CMV-PCR of saliva and plasma, and CMV culture of urine. CMV positive saliva samples were analyzed for genotypes for CMV envelope glycoproteins gB (UL55), and gH (UL75) by genotype specific real-time PCR, and gN (UL73) by cloning and sequencing RESULTS: At 3 months age 40/40 saliva and urine samples, and 19/40 plasma samples were positive for CMV. At 18 months age all urine samples tested (33/33), 9/37 of saliva samples, and 2/34 plasma samples were positive for CMV. The genotype distribution did not differ from the published data CONCLUSIONS: The urinary virus shedding is more persistent than salivary shedding in children with cCMV. The genotype distribution was similar to previous literature and does not explain the low disease burden of cCMV in our population.


Assuntos
Infecções por Citomegalovirus/diagnóstico , Citomegalovirus/genética , Proteínas do Envelope Viral/genética , Eliminação de Partículas Virais , Infecções Assintomáticas , Estudos de Coortes , Citomegalovirus/classificação , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/congênito , Infecções por Citomegalovirus/urina , Finlândia , Genótipo , Humanos , Lactente , Recém-Nascido , Triagem Neonatal , Saliva/virologia , Carga Viral
18.
Pediatr Blood Cancer ; 67(2): e27999, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31674724

RESUMO

BACKGROUND: Children with central nervous system (CNS) toxicity during therapy for acute lymphoblastic leukaemia (ALL) are at risk for treatment modifications, long-term sequelae and even higher mortality. A better understanding of CNS symptoms and their complications improves the potential to prevent and treat them. METHODS: Patient files from 649 children treated with Nordic Society of Pediatric Hematology and Oncology ALL92 and ALL2000 protocols in Finland were reviewed retrospectively for any acute CNS symptom. Detailed data on symptoms, examinations and treatment of the underlying CNS complications were collected from the medical records. Disease-related and outcome data were retrieved from the Nordic leukaemia registry. RESULTS: Altogether, 13% (86) of patients with ALL had acute CNS symptoms. Most symptoms (64%) occurred during the first 2 months of therapy. Posterior reversible encephalopathy syndrome was the most frequent complication (4.5%). Cerebrovascular events were diagnosed in 10 cases (1.6%), while methotrexate-related stroke-like syndrome (SLS) was observed in only one patient (0.2%). CNS symptoms due to systemic or unclear conditions, especially sepsis, were important for differential diagnosis. CNS leukaemia was associated with CNS symptoms (hazard ratio [HR] = 4.03; P = .003), and epilepsy was a common sequel of CNS complications (19%). CONCLUSIONS: Acute CNS symptoms are common during ALL therapy, occurring mainly during the first 2 months of treatment. Patients with CNS leukaemia at diagnosis are at a higher risk for CNS toxicity. Despite intensive CNS-directed methotrexate treatment, SLS was diagnosed extremely rarely in our series.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças do Sistema Nervoso Central/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Doenças do Sistema Nervoso Central/induzido quimicamente , Criança , Feminino , Seguimentos , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
19.
J Adolesc Young Adult Oncol ; 8(5): 593-601, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31063432

RESUMO

Purpose: Childhood brain tumors (CBTs) and their treatment increase the risk of secondary neoplasms (SNs). We studied the incidence of secondary craniospinal tumors with magnetic resonance imaging (MRI) screening in a national cohort of survivors of CBT treated with radiotherapy, and we analyzed the Finnish Cancer Registry (FCR) data on SNs in survivors of CBT with radiotherapy registered as a part of the primary tumor treatment. Methods: A total of 73 survivors of CBT participated in the MRI study (mean follow-up of 19 ± 6.2 years). The incidence of SNs in a cohort of CBT patients (N = 569) was retrieved from the FCR (mean follow-up of 11 ± 12.9 years). Brain tumors were diagnosed at age ≤16 years between the years 1970 and 2008 in the clinical study and the years 1963 and 2010 in the FCR population. Results: Secondary brain tumors, meningiomas in all and schwannoma in one, were found in 6 of the 73 (8.2%) survivors with a mean of 23 ± 4.3 years after the diagnosis of the primary tumor. The cumulative incidence was 10.2% (95% confidence interval [CI] 3.9-25.1) in 25 years of follow-up. In the FCR data, the 25-year cumulative incidence of SNs was 2.4% (95% CI 1.3-4.1); only two brain tumors, no meningiomas, were registered. Conclusion: Survivors of CBT treated with radiotherapy have a high incidence of meningiomas, which are rarely registered in the FCR.


Assuntos
Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Meningioma/etiologia , Neoplasias Induzidas por Radiação/etiologia , Neoplasias Encefálicas/patologia , Criança , Feminino , Humanos , Masculino , Meningioma/patologia , Neoplasias Induzidas por Radiação/patologia , Fatores de Risco
20.
Clin Neurophysiol ; 130(5): 759-766, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30904770

RESUMO

OBJECTIVE: The unspecific symptoms of neonatal stroke still challenge its bedside diagnosis. We studied the accuracy of routine electroencephalography (EEG) and simultaneously recorded somatosensory evoked potentials (EEG-SEP) for diagnosis and outcome prediction of neonatal stroke. METHODS: We evaluated EEG and EEG-SEPs from a hospital cohort of 174 near-term neonates with suspected seizures or encephalopathy, 32 of whom were diagnosed with acute ischemic or hemorrhagic stroke in MRI. EEG was scored for background activity and seizures. SEPs were classified as present or absent. Developmental outcome of stroke survivors was evaluated from medical records at 8- to 18-months age. RESULTS: The combination of continuous EEG and uni- or bilaterally absent SEP (n = 10) was exclusively seen in neonates with a middle cerebral artery (MCA) stroke (specificity 100%). Moreover, 80% of the neonates with this finding developed with cerebral palsy. Bilaterally present SEPs did not exclude stroke, but predicted favorable neuromotor outcome in stroke survivors (positive predictive value 95%). CONCLUSIONS: Absent SEP combined with continuous EEG background in near-term neonates indicates an MCA stroke and a high risk for cerebral palsy. SIGNIFICANCE: EEG-SEP offers a bedside method for diagnostic screening and a reliable prediction of neuromotor outcome in neonates suspected of having a stroke.


Assuntos
Encéfalo/fisiopatologia , Paralisia Cerebral/diagnóstico , Potenciais Somatossensoriais Evocados/fisiologia , Acidente Vascular Cerebral/diagnóstico , Paralisia Cerebral/etiologia , Paralisia Cerebral/fisiopatologia , Eletroencefalografia , Feminino , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/fisiopatologia
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