Expanding the phenotype of DNAJC30-associated Leigh syndrome.

Leigh syndrome (LS) is a progressive neurodegenerative disease, characterized by extensive clinical, biochemical, and genetic heterogeneity. Recently, biallelic variants in DNAJC30 gene, encoding a protein crucial for the repair of mitochondrial complex I subunits, have been associated with Leber hereditary optic neuropathy and LS. It was suggested that clinical heterogeneity of DNAJC30-associated mitochondrial disease may be attributed to digenic inheritance. We describe three Polish patients, a 9-year-old boy, and female and male siblings, aged 17 and 11 years, with clinical and biochemical manifestations of LS. Exome sequencing (ES) identified a homozygous pathogenic variant in DNAJC30 c.152A>G, p.(Tyr51Cys) in the 9-year-old boy. In the siblings, ES identified two DNAJC30 variants: c.152A>G, p.(Tyr51Cys) and c.130_131del, p.(Ser44ValfsTer8) in a compound heterozygous state. In addition, both siblings carried a novel heterozygous c.484G>T, p.(Val162Leu) variant in NDUFS8 gene. This report provides further evidence for the association of DNAJC30 variants with LS. DNAJC30-associated LS is characterized by variable age at onset, movement disorder phenotype and normal or moderately elevated blood lactate level. Identification of a candidate heterozygous variant in NDUFS8 supports the hypothesis of digenic inheritance. Importantly, DNAJC30 pathogenic variants should be suspected in patients with LS irrespective of optic nerve involvement.

The PURPLE N study: objective and perceived nutritional status in children and adolescents with cerebral palsy.

PURPOSE: To obtain information on characteristics, management, current objective nutritional status and perception of nutritional status of children with cerebral palsy (CP) from healthcare professionals (HCPs) and caregivers. MATERIALS AND METHODS: A detailed survey of several items on eight main topics (general characteristics, motor function, comorbidities, therapies, anthropometry, feeding mode and problems and perceived nutritional status) was developed and tested for the study. Correlation between nutritional status and Gross Motor Function Classification System (GMFCS) levels was assessed using continuous variables (Z-scores for weight-for-age, height-for-age, weight-for-height, and body mass index-for-age), and categorical variables (being malnourished, stunted, or wasted). HCP and caregiver perceptions of the child's nutritional status as well as agreement between perceived and objective nutritional status and agreement between perceived nutritional status and concerns about the nutritional status were analyzed. RESULTS: Data were available for 497 participants from eight European countries. Poorer nutritional status was associated with higher (more severe) GMFCS levels. There was minimal agreement between perceived and objective nutritional status, both for HCPs and caregivers. Agreement between HCP and caregiver perceptions of the child's nutritional status was weak (weighted kappa 0.56). However, the concerns about the nutritional status of the child were in line with the perceived nutritional status. CONCLUSIONS: The risk of poor nutritional status is associated with more severe disability in children and adolescents with CP. There is a mismatch between HCP and caregiver perceptions of participants' nutritional status as well as between subjective and objective nutritional status. Our data warrant the use of a simple and objective screening tool in daily practice to determine nutritional status in children and adolescents with CP. Clinical trial registration: ClinicalTrials.gov Identifier: NCT03499288 (https://clinicaltrials.gov/ct2/show/NCT03499288). IMPLICATIONS FOR REHABILITATIONUse of the ESPGHAN recommendations and simple screening tools in daily practice is needed to improve nutritional care for individuals with CP.Attention should be paid to the differences in the perception of nutritional status of individuals with CP between professionals and caregivers to improve appropriate referral for nutritional support.Objective measures rather than the professional's perception need to be used to define the nutritional status of individuals with CP.

Coincidence of PTPN22 c.1858CC and FCRL3 -169CC genotypes as a biomarker of preserved residual ß-cell function in children with type 1 diabetes.

BACKGROUND: Genotype-phenotype studies in type 1 diabetes (T1DM) patients are needed for further development of therapy strategies. OBJECTIVE: Our aims were to investigate the distribution of selected PTPN22 and FCRL3 gene polymorphisms and their associations with clinical course of disease in children with newly diagnosed T1DM from the Pomeranian region of Poland. SUBJECTS/METHODS: The prospective, longitudinal study of 147 children with newly diagnosed T1DM-autoimmune subtype was conducted. The PTPN22 c.1858T>C (rs2476601) and FCRL3 -169C>T (rs7528684) polymorphisms were analyzed using polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP) and DNA sequencing. The frequencies of genotypes were compared between the study and population-matched control group (327 random anonymous samples from the Pomeranian region). Selected patients underwent a 24-monthly follow up [periodic re-evaluation of fasting C-peptide concentration (FCP) and hemoglobin A1c (HbA1c ) level]. RESULTS: A significantly lower coincidence of the PTPN22 c.1858CC and FCRL3 -169CC genotypes was found in the study group compared with controls (P = 0.04). The PTPN22 c.1858CC and FCRL3 -169CC genotype combination, restricted to female patients only, was associated with well-preserved residual ß-cell function throughout the entire follow up (prolonged FCP level increase up to the sixth month of disease, with further very stable dynamics-FCP median level ≥0.67 ng/mL without significant decrease up to the 24th month). HbA1c levels in this subgroup also remained the lowest during the observation period. CONCLUSIONS/INTERPRETATION: Ascertained phenomenon could be explained by an interacting mechanism of the two polymorphisms through estrogen-regulated nuclear factor kappa B signaling in regulatory T (Treg ) lymphocytes. This hypothesis, if confirmed, may lead to further development of Treg administration-based therapies.

[Pathological daytime sleepiness in an 11-year old girl receiving growth hormone treatment previously cured from craniopharyngioma]. / Napady patologicznej sennosci dziennej u 11-letniej dziewczynki leczonej ludzkim rekombinowanym hormonem wzrostu po zakonczonym leczeniu z powodu czaszkogardlaka.

UNLABELLED: An 11-year old girl with multihormonal pituitary deficiency previously cured from craniopharyngioma was admitted to the endocrinology Department because of pathological daytime sleepiness. At the age of 7 she had undergone brain tumor surgery with adjuvant radiotherapy (complete dose of 5400 cGy). She had been given replacement therapy of thyroid hormone, cortisol and adiuretin. At the age of 10 years she had started growth hormone (rGH) treatment. After a period of four months of rGH replacement therapy the girl's mother had observed symptoms of excessive daytime sleepiness with a tendency to escalation. MRI of the brain had been performed; no progression has been shown. After 10 months from the start of rGH replacement therapy was referred to the endocrinology department. On the basis of laboratory findings electrolyte and hormonal abnormalities were excluded. On physical examination, the girl manifested massive tonsillar hypertrophy. It was disclosed that she developed obstructive sleep apnea with the drop of oxygen saturation to 60%. The patient was qualified to adenotonsillectomy. There was a spectacular postoperative improvement observed with no future episodes of night apnea and daytime sleepiness. In our opinion, the rGH treatment in our patient induced hypertrophy of the tonsils and adenoid, which led to obstructive sleep apnea syndrome with compensatory daytime sleepiness. CONCLUSIONS: Obstructive sleep apnea syndrome with compensatory daytime sleepiness may occur in children on rGH replacement therapy. During rGH therapy children should be regularly examined by a laryngologist.

Comparing the effect of hydroxyethyl starch 130/0.4 with balanced crystalloid solution on mortality and kidney failure in patients with severe sepsis (6S--Scandinavian Starch for Severe Sepsis/Septic Shock trial): study protocol, design and rationale for a double-blinded, randomised clinical trial.

BACKGROUND: By tradition colloid solutions have been used to obtain fast circulatory stabilisation in shock, but high molecular weight hydroxyethyl starch (HES) may cause acute kidney failure in patients with severe sepsis. Now lower molecular weight HES 130/0.4 is the preferred colloid in Scandinavian intensive care units (ICUs) and 1st choice fluid for patients with severe sepsis. However, HES 130/0.4 is largely unstudied in patients with severe sepsis. METHODS/DESIGN: The 6S trial will randomize 800 patients with severe sepsis in 30 Scandinavian ICUs to masked fluid resuscitation using either 6% HES 130/0.4 in Ringer's acetate or Ringer's acetate alone. The composite endpoint of 90-day mortality or end-stage kidney failure is the primary outcome measure. The secondary outcome measures are severe bleeding or allergic reactions, organ failure, acute kidney failure, days alive without renal replacement therapy or ventilator support and 28-day and 1/2- and one-year mortality. The sample size will allow the detection of a 10% absolute difference between the two groups in the composite endpoint with a power of 80%. DISCUSSION: The 6S trial will provide important safety and efficacy data on the use of HES 130/0.4 in patients with severe sepsis. The effects on mortality, dialysis-dependency, time on ventilator, bleeding and markers of resuscitation, metabolism, kidney failure, and coagulation will be assessed. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00962156.

Difficulties or mistakes in diagnosing type 1 diabetes in children?--demographic factors influencing delayed diagnosis.

BACKGROUND: Diabetic ketoacidosis (DKA) development in children with new-onset type 1 diabetes (T1DM) is often the main consequence of delayed diagnosis. The aim of the study was to estimate the frequency of difficulties in T1DM diagnosis and to investigate if and how the demographic factors (gender, patient's age at presentation, family history of T1DM, level of maternal education, place of residence, and health service unit the patient called at) have any influence on diagnostic delays. SUBJECTS AND METHODS: Retrospective analysis of 474 children (243 boys-51.27% and 231 girls -48.73%) with new-onset T1DM aged below 17 yr and living in the Pomeranian region of Poland was carried out. The delay in diagnosis was recognized if the patient was not diagnosed on the first visit because of omission, wrong interpretation of main diabetic symptoms, exclusive treatment of additional signs, or concomitant diseases. RESULTS: Difficulties in diagnosing T1DM were found in 67 cases (14.13%) and they are the main cause of DKA development in these children (p = 0.00). Among the examined demographic factors, mainly the patient's age at presentation has a significant influence on diagnostic delays (p = 0.01), especially in children below 2 yr (p = 0.00). Most frequently family doctors were responsible for wrong preliminary diagnosis. CONCLUSIONS: Difficulties in diagnosing T1DM are a significant cause of DKA development in children with new-onset disease. Patient's age at presentation is the main risk factor of delayed diagnosis, especially in children below 2 yr. The increase in awareness among pediatricians concerning the possibility of T1DM development in children is needed.

Difficulties or mistakes in diagnosing type 1 diabetes mellitus in children? The consequences of delayed diagnosis.

INTRODUCTION: Delayed diagnosis is one of the causes of diabetic ketoacidosis (DKA) development in many children with new-onset of type 1 diabetes mellitus (T1DM). THE AIM: of the study was to analyse difficulties in diagnosing T1DM and establish if delayed recognition is the main risk factor of diabetic ketoacidosis (DKA) in children with newly diagnosed T1DM. MATERIALS AND METHODS: Retrospective analysis of 335 children with new-onset T1DM, aged below 17 years and living in the Pomeranian region of Poland, was carried out. The delay in diagnosis was recognized if the patient was not diagnosed on the first visit because of omission, wrong interpretation of symptoms, exclusive treatment of additional diabetic signs or concomitant diseases. RESULTS: Difficulties in diagnosing T1DM were found in 54 cases (16.12%). The initial diagnosis was wrongly categorized as respiratory system infection (46.3%), perineal candidiasis (16.6%), gastroenteritis (16.6%), urinary tract infection (11.1%), stomatitis (11.1%), appendicitis (3.7%). Duration of symptoms (mean 14 days) and glycated haemoglobin level did not significantly correspond with diagnostic delay. DKA was significantly more frequent in children with delayed diagnosis - 33 patients (61.11%) (p=0.0005). The infection preceding diagnosis of T1DM, more common among children with delayed recognition, did not affect the duration of symptoms or affect characteristicly more frequent DKA development in children with diagnostic delay. CONCLUSIONS: No significant associations between diagnostic delay and duration of diabetic symptoms as well as glycated haemoglobin level exclude possibility of delayed diagnosis because of slow development of diabetic symptoms. Significantly more frequent DKA development in children with delayed recognition, irrespective of infection preceding diagnosis, and no confirmation that younger patient's age predisposes to quick increase of DKA point out that the main risk factor for DKA development in the research group was diagnostic delay.