Homozygous mutation in the Neurofascin gene affecting the glial isoform of Neurofascin causes severe neurodevelopment disorder with hypotonia, amimia and areflexia.

The Neurofascins (NFASCs) are a family of proteins encoded by alternative transcripts of NFASC that cooperate in the assembly of the node of Ranvier in myelinated nerves. Differential expression of NFASC in neurons and glia presents a remarkable example of cell-type specific expression of protein isoforms with a common overall function. In mice there are three NFASC isoforms: Nfasc186 and Nfasc140, located in the axonal membrane at the node of Ranvier, and Nfasc155, a glial component of the paranodal axoglial junction. Nfasc186 and Nfasc155 are the major isoforms at mature nodes and paranodes, respectively. Conditional deletion of the glial isoform Nfasc155 in mice causes severe motor coordination defects and death at 16-17 days after birth. We describe a proband with severe congenital hypotonia, contractures of fingers and toes, and no reaction to touch or pain. Whole exome sequencing revealed a homozygous NFASC variant chr1:204953187-C>T (rs755160624). The variant creates a premature stop codon in 3 out of four NFASC human transcripts and is predicted to specifically eliminate Nfasc155 leaving neuronal Neurofascin intact. The selective absence of Nfasc155 and disruption of the paranodal junction was confirmed by an immunofluorescent study of skin biopsies from the patient versus control. We propose that the disease in our proband is the first reported example of genetic deficiency of glial Neurofascin isoforms in humans and that the severity of the condition reflects the importance of the Nfasc155 in forming paranodal axoglial junctions and in determining the structure and function of the node of Ranvier.

The evolution of home mechanical ventilation in poland between 2000 and 2010.

BACKGROUND: Home mechanical ventilation (HMV) is a routine method of treatment for patients with chronic ventilatory failure. Over the last 20 y, a marked development in HMV has been noted in terms of its prevalence and the changing proportion of patients with various indications. However, data on HMV come exclusively from the developed countries of Europe and North America. Nowadays, we can see the emergence of HMV in less developed countries. This study aimed to describe the development of HMV in Poland. METHODS: Data from the largest HMV centers were retrospectively evaluated with regard to cause of respiratory failure, ventilation technique, and characteristics of the HMV-implementing institution. RESULTS: The number of subjects treated with HMV increased from 8 in 2000 to 928 in 2010. Neuromuscular diseases remained the main indication. However, their relative contribution decreased from 100 to 51% in favor of pulmonary diseases (an increase from 0 to 21%) and hypoventilation syndromes (0% in 2000 and 11% in 2010). The majority of the HMV population treated between 2000 between 2008 was ventilated by tracheostomy; however, since 2007, the percentage of subjects on noninvasive ventilation significantly increased and was equal to the number of tracheostomized subjects. HMV was initiated mainly in ICUs. However, their role systematically diminished, and an increasing number of subjects were recruited in respiratory departments. CONCLUSIONS: The prescription pattern of HMV in Poland has evolved, and there is a clear shift from neuromuscular to respiratory diseases. The prevalence of ventilation via tracheostomy still remains very high in comparison with other European countries. The Polish experience could be useful for countries with emerging HMV care systems.

[Prevalence of home mechanical ventilation in Poland]. / Rozpowszechnienie wentylacji mechanicznej w warunkach domowych w Polsce.

INTRODUCTION: Home mechanical ventilation (HMV) is increasingly used in the treatment of chronic respiratory failure thanks to rapid technological development, increasing number of elderly people and extension of indications. The aim of the study was to assess: prevalence of HMV in Poland, the proportions of lung disease and neuromuscular patients using HMV and the type of interface (invasive v. non-invasive). MATERIAL AND METHODS: The questionnaire was send to all institutions providing HMV in Poland and to regional departments of National Health System (NHS). RESULTS: All NHS departments responded. They reported 846 HMV users, 31% of children. The prevalence of HMV in Poland was assessed as 2,2 patient per 100.000 population without striking differences between provinces. Among 39 HMV centers in Poland 12 (31%) answered. They reported 206 patients (24% of all HMV users). Proportion of ventilation mode consisted of 59% (122 pts) treated via a tracheostomy and 41% (84 pts) with non invasive ventilation (NIV). 168 patients (82%) had neuromuscular diseases (ND), majority of them muscular dystrophy - 57 patients ( 34% of ND) and amyotrophic lateral sclerosis - 39 patients (23% of ND). There were only 38 patients (18%) with lung and thoracic cage diseases: 17 with COPD and 10 with kyphoscoliosis. CONCLUSIONS: The prevalence of HMV treatment in Poland has developed dramatically in the last decade, but is still very low comparing to other European countries, especially due to very low number of patients with lung and chest wall diseases. The prevalence of invasive mode of ventilation is extremely high. The most important factors which inhibit development of HMV in Poland are: omission of respiratory physicians in the process of qualification, lack of national guidelines, sophisticated demands for HMV providers. The awareness of the need of HMV especially in patients with respiratory failure due to obesity hypoventilation syndrome and restrictive lung diseases should be increased among chest physicians.

The anti-asparagines antibodies correlate with L-asparagines activity and may affect clinical outcome of childhood acute lymphoblastic leukemia.

The primary aim of the study was to evaluate the importance of anti-asparaginase antibodies for l-asparaginase activity in children with standard and medium risk acute lymphoblastic leukemia (ALL). Forty-seven children with newly diagnosed ALL were included into the prospective study. Enzyme activity and the presence of anti-asparaginase antibodies (IgG and IgM class) were determined. Anti-asparaginase antibodies were identified in 13/47 (IgM class) and 10/47 (IgG class) patients in the induction and in 19/47 (IgM class) and 20/47 (IgG class) patients in the reinduction phase of treatment. The enzyme activity was lower in patients that were positive for anti-asparaginase antibodies, especially in reinduction phase (median 37 (20 - 180) vs 355 (141 - 499), p = 0.001). An association between anti-asparaginase antibodies and the allergic reaction to the drug was found. Besides, the children who developed anti-asparaginase antibodies in the induction phase of treatment showed lower event-free survival as well as overall survival in comparison with children without antibodies. Since our study was carried out in a small number of patients, this observation is only speculative and needs to be confirmed by a further study on a larger sample size, with multivariable analysis. However, our data suggest that L-asparaginase activity together with anti-asparaginase antibodies measurements may become useful for effective therapy of ALL.

[Prognosis of clinical course of primary brain tumours in children in relationship to the duration and characteristic features of initial clinical symptoms]. / Prognozowanie przebiegu klinicznego pierwotnych guzów mózgu u dzieci w odniesieniu do dlugosci trwania i charakteru wstepnych objawów klinicznych.

UNLABELLED: Primary tumours of the central nervous system belong to the most frequently occurring neoplastic diseases in paediatric patients. During the initial phase of disease development, the clinical symptoms of brain tumours might suggest disorders of other organs and their diagnosis is frequently delayed in relation to therapeutic possibilities. The aim of the study was to analyse the characteristic features and duration of preliminary symptoms arising due to brain tumours in paediatric patients treated in a single centre and to try to assess their prognostic significance for recurrence and death. MATERIAL AND METHODS: We performed a retrospective assessment of the characteristic features of preliminary symptoms of brain tumours in 81 paediatric patients (45 female, 35 male) in the age range of 1.5 month - 17.2 years. Those characteristic features included the duration of symptoms until diagnosis (Pre-Diagnostic Symptoms Interval, PSI) and their correlation with the tumour type, its localization and size at the moment of diagnosis. RESULTS: The mean duration of symptoms in the studied group was 3 months. In nearly 45% of patients PSI was longer then 3 months and in 17,5% it was over 6 months. The predominant preliminary disease symptoms were the symptoms of increased intracranial pressure (n=56, 69,1%) The longer PSI correlated with the disease recurrence rate (p=0.024) and death rate (p=0.04). When PSI was longer then 6 months, all the tumours diagnosed were larger then 30 mnm, however no relationship was found between PSI duration and the tumor size (p=0.35). There was no correlation between the tumour size and the frequency of death (p=0.8), but in patients with tumours smaller then 30 mm in their greatest dimension, the recurrence of the neoplastic process was more frequent. CONCLUSIONS: Duration of preliminary symptoms may have an effect on the tumour recurrence and on the rate of death in paediatric patients with brain tumours. Early diagnosis plays an evident role in prognosis.

[Factors affecting C-peptide level during the first year of type 1 diabetes in children]. / Uwarunkowania stezenia peptydu C w pierwszym roku klinicznie jawnej cukrzycy typu 1 u dzieci.

BACKGROUND: C-peptide level is the most reliable factor evaluating the endogenous insulin secretion in patients with type 1 diabetes. OBJECTIVES: The aim of the study was to investigate whether the age at onset, gender, presence of autoantibodies and ketoacidosis at diagnosis and insulin requirement, HbA1c levels could be applied to predict the C-peptide levels in the first year of type 1 diabetes in children. MATERIAL AND METHODS: 122 type 1 diabetic children, aged: 2-18 years (average 11.2), 44 female and 78 male were studied. Fasting C-peptide levels were examined by radioimmunoassay at diagnosis, after 10 days and after 1, 2, 3, 6 and 12 months of disease. At diagnosis islet cell antibodies (ICA) were detected by indirect immunofluorescence, antibodies to glutamic acid decarboxylase (GADA) and tyrosine phosphatase antibodies (IA2A) were measured by microradioimmunoprecipitation assay. RESULTS: Age at onset was positively correlated to C-peptide levels at each evaluated point of the disease (r=0.3-0.46, p<0.0001). One year after diagnosis C-peptide levels decreased in ICA(+) (p<0.04) and GADA(+) (p<0.002) patients but not in ICA(-) or GADA(-) children. There was no significant difference between the IA2A-positive and negative subjects in the C-peptide levels at 12th month of disease. C-peptide level was also related to ketoacidosis at diagnosis, insulin requirement and HbA1c levels during the first year of type 1 diabetes. Logistic regression analysis showed that male, younger age, low pH, higher HbA1c and insulin requirement at onset were associated with decreased C-peptide level at diagnosis (p<0.00002). CONCLUSIONS: Young age, presence of diabetes-related autoantibodies and hyperglycaemia with severe acidosis at the disease onset may be associated with a decreased residual insulin secretion in type 1 diabetes in children.

Development of anti-asparaginase antibodies in childhood acute lymphoblastic leukemia.

L-asparaginase is a basic agent of antileukemic therapy, but allergic reactions against the drug and the development of anti-asparaginase antibodies are significant side-effects. The aim of our study was to estimate the presence of anti-asparaginase antibodies and to correlate the results with clinically apparent allergic reactions and with L-asparaginase activity during the treatment. We examined 13 children with newly diagnosed acute lymphoblastic leukemia (ALL), treated according to the Polish Pediatric Leukemia/Lymphoma Group protocol, based on ALL-BFM 95. Enzyme activity was estimated in serum samples, collected before each L-asparaginase administration, using the photometrical method. Anti-asparaginase antibody concentration was measured by enzyme-linked immunosorbent assay (ELISA) at the two time points: at the last day of L-asparaginase treatment in the induction and the reinduction phase. The mean L-asparaginase activity was 273 IU/L in the induction phase; no anti-asparaginase antibodies in this phase of treatment were found. The mean L-asparaginase activity was 425 IU/L in the reinduction phase of treatment; in five children anti-asparaginase antibodies were detected. In four of these five children low L-asparaginase activity and/or allergic reactions against L-asparaginase were noted. Our observations suggest a correlation between the presence of anti-asparaginase antibodies and L-asparaginase activity in childhood ALL.

[Prognostic value of humoral and metabolic markers as an evaluation of risk for developing type 1 diabetes]. / Wartosc prognostyczna humoralnych i metabolicznych markerów w ocenie ryzyka rozwoju klinicznej postaci cukrzycy typu 1.

Clinical symptoms of type 1 diabetes are preceded by a long period of prediabetes stage characterised by anti-islet antibodies occurrence as well as insulin and C-peptide secretion disturbances. The aim of this study was to define the prognostic value of type 1 diabetes antiislet humoral markers (ICA, anti-GAD, anti-IA2 and IAA) and to find out thresholds for insulin and C-peptide levels at which clinically overt type 1 diabetes develops. Antiislet antibodies, serum C-peptide and insulin were determined in 86 children who, considering their antiislet autoantibodies levels, were classified as prediabetics (mean value of the observation period: 50 months). 8 (9.3%) children, who after a mean time of 35 months of prediabetes stage developed clinically overt type 1 diabetes, were selected from this group. ICA were determined by indirect immunofluorescence; anti-GAD and IAA by radioimmunoprecipitation. C-peptide and insulin levels were evaluated by radioimmunologic assays (CIS Bio International, France). Kaplan-Meier life table analysis revealed pEFS=0.89 after 92 months' observation. The risk of developing diabetes within 80 months was established. For children with positive ICA the risk rate was 0.21, for ICA and anti-GAD positive individuals - 0.39, and for ICA and IA2 positive - 0.74. A significant difference in insulin and C-peptide levels was found between children who developed clinically overt type 1 diabetes and those in prediabetes stage (9.90 vs. 21.45 micro U/ml, p<0.008; 0.34 vs. 0.67 pM/ml, p<0.001 respectively). For both hormones thresholds for high risk of developing clinically overt diabetes were pointed out. Using ROC method the threshold for insulin was determined at 12.9 micro U/ml, for C-peptide at 0.45 pM/ml. Not only the presence and levels of autoantibodies but also the plasma concentrations of C-peptide and insulin are important prognostics of clinical onset of type 1 diabetes mellitus.