Late Onset Of Symptoms Research Articles

New Approaches to Tay-Sachs Disease Therapy.

Tay-Sachs disease belongs to the group of autosomal-recessive lysosomal storage metabolic disorders. This disease is caused by β-hexosaminidase A (HexA) enzyme deficiency due to various mutations in α-subunit gene of this enzyme, resulting in GM2 ganglioside accumulation predominantly in lysosomes of nerve cells. Tay-Sachs disease is characterized by acute neurodegeneration preceded by activated microglia expansion, macrophage and astrocyte activation along with inflammatory mediator production. In most cases, the disease manifests itself during infancy, the “infantile form,” which characterizes the most severe disorders of the nervous system. The juvenile form, the symptoms of which appear in adolescence, and the most rare form with late onset of symptoms in adulthood are also described. The typical features of Tay-Sachs disease are muscle weakness, ataxia, speech, and mental disorders. Clinical symptom severity depends on residual HexA enzymatic activity associated with some mutations. Currently, Tay-Sachs disease treatment is based on symptom relief and, in case of the late-onset form, on the delay of progression. There are also clinical reports of substrate reduction therapy using miglustat and bone marrow or hematopoietic stem cell transplantation. At the development stage there are methods of Tay-Sachs disease gene therapy using adeno- or adeno-associated viruses as vectors for the delivery of cDNA encoding α and β HexA subunit genes. Effectiveness of this approach is evaluated in α or β HexA subunit defective model mice or Jacob sheep, in which Tay-Sachs disease arises spontaneously and is characterized by the same pathological features as in humans. This review discusses the possibilities of new therapeutic strategies in Tay-Sachs disease therapy aimed at preventing neurodegeneration and neuroinflammation.

Preoperative chemotherapy for intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is often diagnosed in advanced tumor extent because of late onset of symptoms. Thus, many tumors are irresectable at initial presentation. The role of preoperative chemotherapy in initially irresectable ICC is still controversial. The aim was to analyse the effect of preoperative chemotherapy on overall and recurrence-free survival. All patients undergoing surgical exploration for ICC (n = 176) were recorded prospectively (2008–2016). Analyses focussed on application of preoperative chemotherapy and re-evaluation after initially assumed irresectability. Overall and recurrence free survival were analysed using Kaplan Meier model. Perioperative deaths were excluded in survival analyses. Out of 176 explorations 10 patients had received preoperative chemotherapy. 8 patients underwent curative intended resection while in 2 patients resection was not reasonable due to a too small or impaired future liver remnant. Comparing overall survival after resection with (n = 8) and without preoperative chemotherapy (n = 119) no significant difference could be shown (p = 0.754; median OS 17.9 months with [range 1–90] vs. 17.5 months without [range 6–48]). The same result was achieved for recurrence-free survival (n = 0.797). Out of 49 irresectable tumors, diagnosed at exploration, 42 received chemotherapy, but none reached secondary resectability. Patients who received preoperative chemotherapy reaching exploration and curative intended resection have a comparable overall and recurrence-free survival to patients with initially resectable tumors. Therefore, it is important to perform regular re-staging imaging in patients who undergo chemotherapy for irresectable ICC and discuss these cases interdisciplinary at a tertiary center for liver surgery.

Older men with bipolar disorder: Clinical associations with early and late onset illness.

Older adults living with bipolar disorder (BD) include people with early and late onset of symptoms. This study aimed to clarify the cross-sectional and longitudinal clinical associations of BD with early and late onset. Cohort study of 38173 men aged 65-85years followed for up to 17.6years. We used the Western Australian Data Linkage System to establish the presence of BD, as well as diabetes, cardiovascular and renal diseases, cancer, respiratory and gastrointestinal diseases, alcohol use disorder, dementia, and mortality. The causes of death were recorded according to the International Classification of Diseases. We defined late onset BD using 2 different cut-points: 50 and 60years. The prevalence of medical morbidities was greater among participants with than without BD, and cardiovascular diseases were more frequent among those with onset before than after 50years (odds ratio=1.72, 95% confidence interval=1.01, 2.94). Bipolar disorder was associated with increased hazard ratio of dementia and death, but there was no difference between early and late onset participants. Death by suicide or accidents occurred exclusively among BD participants with illness onset <60years, whereas death associated with strokes and neurodegenerative diseases was more frequent among those with illness onset ≥60years than in the general population (HR=2.28, 95% confidence interval=1.34, 3.88). Our results indicate that the clinical associations and outcomes of older adults living with BD are not markedly influenced by age of onset. However, mortality data suggest that differences between older adults with BD onset before and after age 60years should continue to be explored.

Antibody profile may predict outcome in ocular myasthenia gravis.

An unsolved issue remains whether there are clinical and immunological features to predict in a single patient the risk of conversion from ocular Myasthenia Gravis (OMG) to generalized disease (GMG) as 50-60% of patients may progress within 1-2years since onset. Anti-acetylcholine receptor antibodies (AChR Abs) are found in up to 50% of OMG patients; muscle-specific tyrosine kinase antibodies (MuSK-Abs) are present in about 70% of the whole seronegative (SN), who usually develop a severe disease with bulbar involvement. We surveyed a cohort of 175 OMG patients with purely ocular symptoms and we compare the outcome of patients with antibodies to AChR or to MuSK with those seronegative for both Abs (DSN). All patients had purely ocular signs for at least 24months. Gender, age at onset, time to generalization or to worsening in quantitative ocular QMG scores, electrophysiological results were analyzed. Males were 58.9%, females 41.1%. Patients with late onset of symptoms after 50years (LOMG) were 78.3%. We assayed anti-MuSK-Abs in 4.7%, anti-AChR Abs in 38.5%; 57.3% were defined DSN. Thirty-seven patients (21.1%) progressed to GMG during the observational time: 23 were females, 62% of the whole group of the generalized subjects, 75% of MuSK-positive OMG converted to GMG versus the 26.2% of AChR positive and 13.7% of DSN. Statistical analysis showed that gender and presence of antibodies either to AChR or to MuSK were independent predictors of worse outcome; the DSN subjects had lower risk of conversion to GMG.

Extremely hypomorphic and severe deep intronic variants in the ABCA4 locus result in varying Stargardt disease phenotypes.

Autosomal recessive Stargardt disease (STGD1, MIM 248200) is caused by mutations in the ABCA4 gene. Complete sequencing of the ABCA4 locus in STGD1 patients identifies two expected disease-causing alleles in ∼75% of patients and only one mutation in ∼15% of patients. Recently, many possibly pathogenic variants in deep intronic sequences of ABCA4 have been identified in the latter group. We extended our analyses of deep intronic ABCA4 variants and determined that one of these, c.4253+43G>A (rs61754045), is present in 29/1155 (2.6%) of STGD1 patients. The variant is found at statistically significantly higher frequency in patients with only one pathogenic ABCA4 allele, 23/160 (14.38%), MAF = 0.072, compared to MAF = 0.013 in all STGD1 cases and MAF = 0.006 in the matching general population (P < 1 × 10−7). The variant, which is not predicted to have any effect on splicing, is the first reported intronic “extremely hypomorphic allele” in the ABCA4 locus; that is, it is pathogenic only when in trans with a loss-of-function ABCA4 allele. It results in a distinct clinical phenotype characterized by late onset of symptoms and foveal sparing. In ∼70% of cases the variant was allelic with the c.6006-609T>A (rs575968112) variant, which was deemed nonpathogenic. Another rare deep intronic variant, c.5196+1056A>G (rs886044749), found in 5/834 (0.6%) of STGD1 cases is, conversely, a severe allele. This study determines pathogenicity for three noncoding variants in STGD1 patients of European descent accounting for ∼3% of the disease. Defining disease-associated alleles in the noncoding sequences of the ABCA4 locus can be accomplished by integrated clinical and genetic analyses.

Histone deacetylase inhibitor trichostatin A sensitises cisplatin-resistant ovarian cancer cells to oncolytic adenovirus.

Ovarian cancer is often termed a silent killer due to the late onset of symptoms. Whilst patients initially respond to chemotherapy, they rapidly develop chemo-resistance. Oncolytic adenoviruses (OAds) are promising anti-cancer agents engineered to “hijack” the unique molecular machinery of cancer cells enabling tumour-selective viral replication. This allows spread to adjacent cells and amplification of oncolysis within the tumour. OAds represent an excellent opportunity for ovarian cancer therapy via intra-peritoneal delivery, however the efficacy of OAds thus far is limited. Here, we evaluate chromatin (histone) modification in chemo-resistant cells and its relationship to Ad efficacy (wild-type or oncolytic Ad). In contrast to cisplatin-sensitive A2780 cells that show an efficient reduction of cell viability by Ad in the presence of cisplatin, cisplatin-resistant A2780/cp70 cells show diminishing Ad-mediated reduction of cell viability with escalating doses of cisplatin. Histone deacetylase (HDAC)-2 and to a lesser extent HDAC1 were up-regulated in cisplatin-resistant but not cisplatin-sensitive cells. Cisplatin-resistant cells treated with a pan-HDAC inhibitor trichostatin A (TsA) significantly enhanced Ad-mediated reduction of cell viability in the presence of cisplatin. Cells treated with TsA alone did not reduce cell viability suggesting these findings are Ad-dependent. Thus, we identify HDAC inhibition as a potential means to sensitise cisplatin-resistant ovarian cancer cells to virotherapies, an observation that may offer improved outcomes for patients with late stage, chemotherapy-resistant ovarian cancer.

Children with autism spectrum disorders and selective mutism.

BackgroundIt has been suggested that autism spectrum disorder (ASD) might be a “comorbid” condition in selective mutism (SM).MethodsIn this retrospective study, we examined medical records of children with SM diagnosis (n=97) at a medical center specializing in assessment of ASD.ResultsMean age for onset of SM symptoms was 4.5 years and mean age at SM diagnosis was 8.8 years. SM was more common among girls (boy:girl ratio=2.7:1). We found that 63% of the study group had an ASD (no gender difference). The SM group with combined ASD had later onset of symptoms, higher age at diagnosis, more often a history of speech delay, and a higher proportion of borderline IQ or intellectual disability.ConclusionThe results highlight the risk of overlap between ASD and SM.

Characterization of a novel variant in siblings with Asparagine Synthetase Deficiency

Asparagine Synthetase Deficiency (ASD) is a recently described inborn error of metabolism caused by bi-allelic pathogenic variants in the asparagine synthetase (ASNS) gene. ASD typically presents congenitally with microcephaly and severe, often medically refractory, epilepsy. Development is generally severely affected at birth. Tone is abnormal with axial hypotonia and progressive appendicular spasticity. Hyperekplexia has been reported. Neuroimaging typically demonstrates gyral simplification, abnormal myelination, and progressive cerebral atrophy. The present report describes two siblings from consanguineous parents with a homozygous Arg49Gln variant associated with a milder form of ASD that is characterized by later onset of symptoms. Both siblings had a period of normal development before onset of seizures, and development regression. Primary fibroblast studies of the siblings and their parents document that homozygosity for Arg49Gln blocks cell growth in the absence of extracellular asparagine. Functional studies with these cells suggest no impact of the Arg49Gln variant on basal ASNS mRNA or protein levels, nor on regulation of the gene itself. Molecular modelling of the ASNS protein structure indicates that the Arg49Gln variant lies near the substrate binding site for glutamine. Collectively, the results suggest that the Arg49Gln variant affects the enzymatic function of ASNS. The clinical, cellular, and molecular observations from these siblings expand the known phenotypic spectrum of ASD.

Late-Onset ADHD: Understanding the Evidence and Building Theoretical Frameworks.

The traditional definition of Attention-Deficit/Hyperactivity Disorder (ADHD), assuming onset in childhood, has been challenged by evidence from four recent birth-cohort studies that reported most adults with ADHD lacked a childhood categorical ADHD diagnosis. Late onset of symptoms was evaluated in the long-term follow-up of the Multimodal Treatment study of ADHD (MTA). In most cases, other factors were present that discounted the late onset of ADHD symptoms and excluded the diagnosis of ADHD. We offer two theoretical frameworks for understanding the ADHD trajectory throughout the life cycle: (1) the complex phenotype model, and (2) the restricted phenotype model. We conclude that (a) late onset (after age 12) is a valid trajectory for ADHD symptoms, (b) the percentage of these cases with onset after adolescence is yet uncertain, and

Endolymphatic sac tumour in von Hippel-Lindau disease: management strategies.

SUMMARYEndolymphatic sac tumour (ELST) is infrequent, as emerges from small series reported in the literature. It is a slow-growing malignancy with local aggressiveness and a low risk of distant metastases. It is often misdiagnosed because of the late onset of symptoms and difficulty in obtaining a biopsy. Its frequency is higher in von Hippel-Lindau (VHL) disease (a genetic systemic syndrome involving multiple tumours), with a prevalence of around 25%. The diagnosis is based on radiology, with specific patterns on contrast-enhanced MRI and typical petrous bone erosion on bone CT scan. Our experience of ELST in the years between 2012-2015 concerns 7 cases, one of which was bilateral, in patients with VHL disease. Four of the 7 patients underwent 5 surgical procedures at our institution. Each case is described in detail, including clinical symptoms, and the intervals between symptom onset, diagnosis and therapy. Postoperative morbidity was low after early surgery on small tumours, whereas extensive surgery for large tumours was associated with loss of cranial nerve function (especially VII, IX, X). The critical sites coinciding with loss of neurological function were the fallopian canal, jugular foramen, petrous apex and intradural extension into the posterior cranial fossa. Early surgery on small ELST is advocated for patients with VHL disease, in whom screening enables a prompt diagnosis and consequently good prognosis.

Milder clinical and biochemical phenotypes associated with the c.482G>A (p.Arg161Gln) pathogenic variant in cobalamin C disease: Implications for management and screening.

Cobalamin C disease is a multisystemic disease with variable manifestations and age of onset. Genotype-phenotype correlations are well-recognized in this disorder. Here, we present a large cohort of individuals with cobalamin C disease, several of whom are heterozygous for the c.482G>A pathogenic variant (p.Arg161Gln). We compared clinical characteristics of individuals with this pathogenic variant to those who do not have this variant. To our knowledge, this study represents the largest single cohort of individuals with the c.482G>A (p.Arg161Gln) pathogenic variant. A retrospective chart review of 27 individuals from 21 families with cobalamin C disease who are followed at our facility was conducted. 13 individuals (48%) are compound heterozygous with the c.482G>A (p.Arg161Gln) on one allele and a second pathogenic variant on the other allele. Individuals with the c.482G>A (p.Arg161Gln) pathogenic variant had later onset of symptoms and easier metabolic control. Moreover, they had milder biochemical abnormalities at presentation which likely contributed to the observation that 4 individuals (31%) in this group were missed by newborn screening. The c.482G>A (p.Arg161Gln) pathogenic variant is associated with milder disease. These individuals may not receive a timely diagnosis as they may not be identified on newborn screening or because of unrecognized, late onset symptoms. Despite the milder presentation, significant complications can occur, especially if treatment is delayed.

Improving theranostics in pancreatic cancer.

Pancreatic cancer is the fourth most deadly cancer in the United States, and is expected to be the second most deadly by 2030. The major difficulty in treating pancreatic cancer is the late onset of symptoms. Generally, patients show metastatic disease by the time of diagnosis, with a survival rate of 5% beyond 5 years. In patients without metastatic disease, surgical resection increases 5 year survival rate to 25%. The remaining 75% succumb to undetected metastases. Clearly, improvements to both detection, surgical intervention, and therapeutic strategies will be needed to improve patient outcome in pancreatic cancer. Recent literature has been surveyed and atomic models of new therapeutic approaches were generated. Here, we focus on the recent progress employing monoclonal antibodies (mAbs) to target pancreatic cancer associated markers, and more specifically on recent chemical and protein engineering efforts to improve the homogeneity, stability, and administration of mAbs to precisely deliver imaging agents and cytotoxins to sites of disease.

Diagnosis, Course, and Management of Angioedema in Patients With Acquired C1-Inhibitor Deficiency

Acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE) is a rare disease with no prevalence data or approved therapies. To report data on patients with C1-INH-AAE followed at Angioedema Center, Milan (from 1976 to 2015). Diagnostic criteria included history of recurrent angioedema without wheals; decreased C1-INH antigen levels and/or functional activity of C1-INH and C4 antigen less than 50% of normal; late symptom onset (>40 years); no family history of angioedema and C1-INH deficiency. In total, 77 patients (58% females; median age, 70 years) were diagnosed with C1-INH-AAE and 675 patients with hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) (1 patient with C1-INH-AAE/8.8 patients with C1-INH-HAE). Median age at diagnosis was 64 years. Median time between symptom onset and diagnosis was 2 years. Sixteen patients (21%) died since diagnosis, including 1 because of laryngeal edema. Angioedema of the face was most common (N= 63 [82%]), followed by abdomen (N= 51 [66%]), peripheries (N= 50 [65%]), and oral mucosa and/or glottis (N= 42 [55%]). Forty-eight of 71 patients (68%) had autoantibodies to C1-INH. In total, 56 patients (70%) used on-demand treatment for angioedema including intravenous pdC1-INH 2000 U (Berinert, CSL Behring, Marburg, Germany) (N= 49) and/or subcutaneous icatibant 30 mg (Firazyr, Shire; Milano, Italy) (N= 27). Eventually, 8 of 49 patients receiving pdC1-INH became nonresponsive; all had autoantibodies. Thirty-four patients received long-term prophylaxis with tranexamic acid (effective in 29) and 20 with androgens (effectivein 8). The incidence of C1-INH-AAE was 1 for every8.8 patients with C1-INH-HAE. Thirty percent of the deaths were related to the disease. Treatments approved for C1-INH-HAE are effective in C1-INH-AAE, although with minimal differences.

Nanotechnology for delivery of gemcitabine to treat pancreatic cancer.

Pancreatic cancer (PC) is one of the most deadly and quickly fatal human cancers with a 5-year mortality rate close to 100%. Its prognosis is very poor, mainly because of its hostile biological behavior and late onset of symptoms for clinical diagnosis; these bring limitations on therapeutic interventions. Factors contributing for the difficulties in treating PC include: high rate of drug resistance, fast metastasis to different organs, poor prognosis and relapse of the tumor after therapy. After being approved by US FDA 1997, Gemcitabine (Gem) is the first line and the gold standard drug for all stages of advanced PC till now. However, its efficacy is unsatisfactory, mainly due to; its chemical instability and poor cellular uptake, resulting in an extremely short half-life and low bioavailability. To solve this drawbacks and increase the therapeutic outcome important progress has been achieved in the field of nanotechnology and offers a promising and effective alternative. This review mainly focus on the most commonly investigated nanoparticle (NP) delivery systems of Gem for PC treatment and the latest progresses achieved. Novel nanocarriers with better tumor targeting efficiencies and maximum treatment outcome to treat this deadly due are given much attention.

TWIST1 drives cisplatin resistance and cell survival in an ovarian cancer model, via upregulation of GAS6, L1CAM, and Akt signalling.

Epithelial ovarian cancer (EOC) is the most deadly gynaecologic malignancy due to late onset of symptoms and propensity towards drug resistance. Epithelial-mesenchymal transition (EMT) has been linked to the development of chemoresistance in other cancers, yet little is known regarding its role in EOC. In this study, we sought to determine the role of the transcription factor TWIST1, a master regulator of EMT, on cisplatin resistance in an EOC model. We created two Ovcar8-derived cell lines that differed only in their TWIST1 expression. TWIST1 expression led to increased tumour engraftment in mice, as well as cisplatin resistance in vitro. RNA sequencing analysis revealed that TWIST1 expression resulted in upregulation of GAS6 and L1CAM and downregulation of HMGA2. Knockdown studies of these genes demonstrated that loss of GAS6 or L1CAM sensitized cells to cisplatin, but that loss of HMGA2 did not give rise to chemoresistance. TWIST1, in part via GAS6 and L1CAM, led to higher expression and activation of Akt upon cisplatin treatment, and inhibition of Akt activation sensitized cells to cisplatin. These results suggest TWIST1- and EMT-driven increase in Akt activation, and thus tumour cell proliferation, as a potential mechanism of drug resistance in EOC.

Late Onset of Severe Symptoms in a Patient with Wolff-Parkinson-White Syndrome with Misleading ECG Pattern of the Accessory Pathway Origin Undergoing Successful Ablation

The case of a female patient with symptomatic Wolff-Parkinson-White syndrome is presented with very late onset of symptoms at the age of 65 years, who had an apparent left-sided posteroseptal accessory pathway, which was ablated via a right-sided approach. A subepicardial location was strongly suspected within the coronary sinus ostium at the origin of the middle cardiac vein by applying both ECG and fluoroscopic criteria.

Fixation Location and Stability Using the MP-1 Microperimeter in Stargardt Disease: ProgStar Report No. 3

To determine fixation location and fixation stability in Stargardt disease (STGD1) and their association with best-corrected visual acuity (BCVA). Cross-sectional analysis within the multicenter, prospective ProgStar study. A total of 238 patients and 440 eyes with ABCA4-related STGD1. Patients underwent testing with the Nidek MP-1 microperimeter (Nidek Technologies Inc., Gamagōri, Japan). Fixation location was expressed as the eccentricity of the preferred retinal locus (PRL) from the anatomic fovea, fixation stability was expressed as the bivariate contour ellipse area (BCEA), and BCVA was expressed as Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Linear models with generalized estimating equations were used for statistical analysis while accounting for between-eye correlations. Fixation location and fixation stability. Median PRL eccentricity from the fovea was 6° (mean, 6.3°; range, 0°-25°) and median BCEA was 6.31°2 (mean, 12.31°2; range, 0.03°2-365.63°2). Each year of later onset of symptoms of STGD1 was associated with 0.14° more central fixation location (P < 0.0001), but not with fixation stability (P= 0.53). A single linear model best described the relationship between fixation location and BCVA: 1° farther PRL eccentricity was associated with a 2.3-letter loss of BCVA (P < 0.0001). A piecewise linear model best described the relationship between fixation stability and BCVA: for a BCEA less than 2.8°2, an increase in BCEA by 1°2 was associated with a 10.5-letter (ETDRS) lower BCVA (P < 0.0001). For a BCEA 2.8°2 or more, an increase in BCEA by 1°2 was associated with a 0.036-letter (ETDRS) lower BCVA (P= 0.0234). Pearson correlation coefficients between patients' right and left eyes were 0.89 (P < 0.0001) for fixation location and 0.25 (P= 0.0006) for fixation stability. After 10 years of disease duration, 82% of patients had eccentric PRLs in both eyes. We provide the first extensive database of continuous fixation parameters in STGD1 and demonstrate their association with vision. These measures allow for a more comprehensive assessment of retinal function and may serve as potential secondary outcome measures for future treatment trials for STGD1 and other macular diseases.

Characterization of a Leber's hereditary optic neuropathy (LHON) family harboring two primary LHON mutations m.11778G > A and m.14484T > C of the mitochondrial DNA

Leber's hereditary optic neuropathy (LHON) is an inherited mitochondrial disease that usually leads to acute or subacute bilateral central vision loss. In 95% of cases, LHON is caused by one of three primary mutations of the mitochondrial DNA (mtDNA), m.11778G>A in the MT-ND4 gene, m.14484T>C in the MT-ND6 gene, or m.3460G>A in the MT-ND1 gene.Here we characterize clinically, genetically, and biochemically a LHON family with multiple patients harboring two of these primary LHON mutations, m.11778G>A homoplasmic and m.14484T>C heteroplasmic.The unusually low male-to-female ratio of affected family members is also seen among the other patients previously reported with two primary LHON mutations m.11778G>A and m.14484T>C. While the index patient had very late onset of symptoms at 75years and severe visual loss, her two daughters had both onset in childhood (6 and 9years), with moderate to mild visual loss. A higher degree of heteroplasmy of the m.14484T>C mutation was found to correlate with an earlier age at onset in this family.Ours is the first LHON family harboring two primary LHON mutations where functional studies were performed in several affected family members. A more pronounced bioenergetic defect was found to correlate with an earlier age at onset. The patient with the earliest age at onset had a more significant complex I dysfunction than all controls, including the LHON patient with only the m.11778G>A mutation, suggesting a synergistic effect of the two primary LHON mutations in this patient.

Long-Term Outcome of Classic and Incomplete PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis) Syndrome after Tonsillectomy

To compare the effectiveness of tonsillectomy and the long-term outcome of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome in patients fulfilling the classic diagnostic criteria and in those with regularly recurring fever as the only symptom or with onset of symptoms after age 5 years or both. We reviewed the medical records of 3852 children who underwent tonsillectomy between 1990 and 2007 and identified 108 children who did so because of regularly recurring fevers. The patients were invited to an outpatient visit and were classified into 2 groups: those who met (N = 58) and those who did not meet (N = 50) Thomas diagnostic criteria. We then compared the clinical profile and outcome of PFAPA symptoms after tonsillectomy between the 2 groups. In the group that met Thomas criteria, 97% (56/58) had complete resolution of fever episodes after tonsillectomy; in the group that did not meet Thomas criteria (50/50) had complete resolution of fever episodes after tonsillectomy (P = .25). The clinical profile of the periodic fevers and the occurrence of other illnesses during follow-up were similar in both groups. Thomas criteria identified 56 of 106 patients responding to tonsillectomy. Tonsillectomy was an effective treatment for patients with regularly recurring fever episodes who failed to meet the classic Thomas criteria. We suggest that PFAPA syndrome should be suspected and tonsillectomy considered in children with a late onset of symptoms (>5 years of age) or when fever is the only symptom during the episodes.

Age at disease onset and peak ammonium level rather than interventional variables predict the neurological outcome in urea cycle disorders.

Patients with urea cycle disorders (UCDs) have an increased risk of neurological disease manifestation. Determining the effect of diagnostic and therapeutic interventions on the neurological outcome. Evaluation of baseline, regular follow-up and emergency visits of 456 UCD patients prospectively followed between 2011 and 2015 by the E-IMD patient registry. About two-thirds of UCD patients remained asymptomatic until age 12 days [i.e. the median age at diagnosis of patients identified by newborn screening (NBS)] suggesting a potential benefit of NBS. In fact, NBS lowered the age at diagnosis in patients with late onset of symptoms (>28 days), and a trend towards improved long-term neurological outcome was found for patients with argininosuccinate synthetase and lyase deficiency as well as argininemia identified by NBS. Three to 17 different drug combinations were used for maintenance therapy, but superiority of any single drug or specific drug combination above other combinations was not demonstrated. Importantly, non-interventional variables of disease severity, such as age at disease onset and peak ammonium level of the initial hyperammonemic crisis (cut-off level: 500 μmol/L) best predicted the neurological outcome. Promising results of NBS for late onset UCD patients are reported and should be re-evaluated in a larger and more advanced age group. However, non-interventional variables affect the neurological outcome of UCD patients. Available evidence-based guideline recommendations are currently heterogeneously implemented into practice, leading to a high variability of drug combinations that hamper our understanding of optimised long-term and emergency treatment.