The most frequent manifestation in adult hypophosphatasia (HPP) is musculoskeletal pain. The unspecific nature of its clinical presentation may prevent correct diagnosis. The aim of the study was to ...assess the prevalence of ALPL mutations in adult patients treated in rheumatological outpatient facilities with evident musculoskeletal symptoms typical for HPP.
Over a period of 10 years 9,522 patients were screened in the rheumatology outpatient clinic of the Hanusch hospital Vienna. Serum ALP levels ≤ 40 U/L were found in 524 patients. After screening for secondary causes, 73 patients were invited for clinical evaluation. Genetic testing was performed in 23 patients with suspected HPP. Logistic regression models with Firth penalisation were used to estimate the unadjusted and BMI-adjusted association of each clinical factor with HPP.
Mutations in the ALPL gene were observed in 57% of genetically screened patients. Arthralgia, fractures, and pain were the leading symptoms in individuals with ALPL mutation. Chondrocalcinosis (OR 29.12; 95% CI 2.02-1593.52) and dental disease (OR 8.33; 95% CI 0.93-143.40) were associated with ALPL mutation, independent of BMI. Onset of symptoms in patients with ALPL mutation was at 35.1 (14.3) years, with a mean duration from symptoms to diagnosis of 14.4 (8.1) years. Bone mineral density (BMD) and trabecular bone score (TBS) as well as bone turnover markers were not indicative for HPP or ALPL mutation.
HPP can mimic rheumatologic diseases. Thus, HPP should be considered as a possible diagnosis in adult patients presenting with musculoskeletal pain of unknown origin in rheumatology outpatient clinics. In patients with persistently low ALP serum levels and unclear musculoskeletal pain, HPP as the underlying cause has to be considered.
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•Altered bone material in adult XLH patients at micro- and submicroscopic scales.•Decreased area of hypomineralized periosteocytic lesions with conventional therapy.•Increased ...mineralized bone volume and osteonal-like perforations without therapy.•Typical matrix calcium level within or above normal range, independently of therapy.•Osteomalacic matrix lacks pyridinoline cross-links but has elevated lipid content.
X-linked hypophosphatemia (XLH) caused by PHEX mutations results in elevated serum FGF23 levels, renal phosphate wasting and low 1,25-dihydroxyvitamin D. The glycophosphoprotein osteopontin, a potent inhibitor of mineralization normally degraded by PHEX, accumulates within the bone matrix. Conventional therapy consisting of supplementation with phosphate and vitamin D analogs is burdensome and the effects on bone material poorly characterized.
We analyzed transiliac bone biopsies from four adult patients, two of them severely affected due to no diagnosis and no treatment until adulthood. We used light microscopy, qBEI and FTIRI to study histology, histomorphometry, bone mineralization density distribution, properties of the organic matrix and size of hypomineralized periosteocytic lesions.
Non-treatment resulted in severe osteomalacia, twice the amount of mineralized trabecular volume, multiple osteon-like perforations, continuity of lamellae from mineralized to unmineralized areas and distinctive patches of woven bone. Periosteocytic lesions were larger than in treated patients. The latter had nearly normal osteoid thicknesses, although surface was still elevated.
The median calcium content of the matrix was always within normal range, although the percentage of lowly mineralized bone areas was highly increased in non-treated patients, resulting in a marked heterogeneity in mineralization.
Divalent collagen cross-links were evident independently of the mineral content of the matrix. Broad osteoid seams lacked measurable pyridinoline, a mature trivalent cross-link and exhibited considerable acidic lipid content, typically found in matrix vesicles.
Based on our results, we propose a model that possibly integrates the relationship between the observed mineralization disturbances, FGF23 secretion and the known osteopontin accumulation in XLH.
Congenital myasthenic syndromes are clinically and genetically heterogeneous disorders of neuromuscular transmission. Most are treatable, but certain subtypes worsen with cholinesterase inhibitors. ...This underlines the importance of genetic diagnosis. Here, the authors report on cases with genetically proven congenital myasthenic syndromes from Turkey. The authors retrospectively reviewed their experience of all patients with congenital myasthenic syndromes, referred over a 5-year period (2011-2016) to the Child Neurology Department of Dokuz Eylül University, Izmir, Turkey. In addition, PubMed was searched for published cases of genetically proven congenital myasthenic syndromes originating from Turkey. In total, the authors identified 43 (8 new patients, 35 recently published patients) cases. Defects in the acetylcholine receptor (n = 15; 35%) were the most common type, followed by synaptic basal-lamina associated (n = 14; 33%) and presynaptic syndromes (n = 10; 23%). The authors had only 3 cases (7%) who had defects in endplate development. One patient had mutation GFPT1 gene (n = 1; 2%). Knowledge on congenital myasthenic syndromes and related genes in Turkey will lead to prompt diagnosis and treatment of these rare neuromuscular disorders.
The aim of this research is to examine the knowledge levels of classroom teacher candidates about global warming. The survey model was used in the study. The sample of the study consists of a total ...of 324 teacher candidates studying in the Kastamonu University Faculty of Education. The research was carried out in the fall semester of the 2019-2020 academic year. Global warming knowledge scale was used as a data gathering tool. In the analysis of the data, t-test for independent groups, one-way analysis of variance (ANOVA) and Bonferroni test were used. According to the findings, it has been determined that there was a significant difference in favor of female teacher candidates according to the gender variable who have been studying at the fourth grade level. However, when the knowledge levels of classroom teacher candidates studying at different grade levels on global warming were examined, it was determined that there was a significant difference between the scores of the first grade teacher candidates and the second, third and fourth grade teacher candidates in favor of the second, third and fourth grade teacher candidates
The aim of this research is to examine the knowledge levels of classroom teacher candidates about global warming. The survey model was used in the study. The sample of the study consists of a total of 324 teacher candidates studying in the Kastamonu University Faculty of Education. The research was carried out in the fall semester of the 2019-2020 academic year. Global warming knowledge scale was used as a data gathering tool. In the analysis of the data, t-test for independent groups, one-way analysis of variance (ANOVA) and Bonferroni test were used. According to the findings, it has been determined that there was a significant difference in favor of female teacher candidates according to the gender variable who have been studying at the fourth grade level. However, when the knowledge levels of classroom teacher candidates studying at different grade levels on global warming were examined, it was determined that there was a significant difference between the scores of the first grade teacher candidates and the second, third and fourth grade teacher candidates in favor of the second, third and fourth grade teacher candidates
Abstract Pontocerebellar hypoplasias (PCH) represent a heterogeneous group of autosomal recessive neurodegenerative disorders characterized by hypoplasia of the cerebellum and pons, variable cerebral ...involvement, microcephaly, severe delay in cognitive and motor development, and seizures. Seven different subtypes have been reported (PCH1-7) and mutations in three genes, TSEN2 , TSEN34 and TSEN54 encoding three of four subunits of the tRNA splicing endonuclease complex have been found to underlie PCH2, PCH4 and PCH5. PCH2 is characterized by cerebellar hypoplasia affecting the hemispheres more severely than the vermis, progressive cerebral atrophy and microcephaly, dyskinesia, seizures, and death in early childhood. We describe a male patient with progressive microcephaly, severe hypotonia, and myoclonic-tonic seizures. Brain MRI confirmed microcephaly with simplified cortical gyration and revealed hypoplasia of the brainstem, cerebellum and cerebellar vermis. Sequencing of the TSEN2 gene detected the novel missense mutation c.934G > A (p.G312R) on one allele and the first nonsense mutation c.691C > T (p.Q231*) on the second allele. Although the cytosine-to-thymine transition results in introduction of a premature stop codon in the majority of annotated TSEN2 transcript variants, it could represent a splice site mutation (c.517-3C > T) in variant 4. However, by RT-PCR analysis we did not identify mRNAs representing TSEN2 transcript form 4 in leukocyte-derived RNA of the patient and healthy individuals. The clinical phenotype of the patient is comparable with PCH2. However, we noticed decreased cerebral volume with increased extra-axial cerebrospinal fluid spaces and wide-open Sylvian fissures indicating cerebral immaturity that might be associated with the TSEN2 null allele. We conclude that the severity of pontocerebellar hypoplasia in the patient fits PCH2, while the large involvement of the cerebrum better corresponds to PCH4 demonstrating the phenotypic spectrum of PCH2 and 4. To establish a possible genotype–phenotype correlation, more individuals with biallelic TSEN2 mutations need to be investigated.
Patients with a myeloproliferative neoplasm (MPN) sometimes show a chronic myelomonocytic leukemia (CMML)-like phenotype but, according to the 2016 WHO classification, a documented history of an MPN ...excludes the diagnosis of CMML. Forty-one patients with an MPN (35 polycythemia vera (PV), 5 primary myelofibrosis, 1 essential thrombocythemia) and a CMML-like phenotype (MPN/CMML) were comprehensively characterized regarding clinical, hematologic, biologic and molecular features. The white blood cell counts in MPN/CMML patients were not different from CMML patients and PV patients. The hemoglobin values and platelet counts of these patients were higher than in CMML but lower than in PV, respectively. MPN/CMML patients showed myelomonocytic skewing, a typical in vitro feature of CMML but not of PV. The mutational landscape of MPN/CMML was not different from JAK2-mutated CMML. In two MPN/CMML patients, development of a CMML-like phenotype was associated with a decrease in the JAK2 V617F allelic burden. Finally, the prognosis of MPN/CMML (median overall survival (OS) 27 months) was more similar to CMML (JAK2-mutated, 28 months; JAK2-nonmutated 29 months) than to PV (186 months). In conclusion, we show that patients with MPN and a CMML-like phenotype share more characteristics with CMML than with PV, which may be relevant for their classification and clinical management.
Abstract Background To evaluate clinical, genetic, and radiologic features of our patients with muscle-eye-brain disease. Methods The data of patients who were diagnosed with muscle-eye-brain disease ...from a cohort of patients with congenital muscular dystrophy in the Division of Pediatric Neurology of Dokuz Eylül University School of Medicine and Gaziantep Children's Hospital between 2005 and 2013 were analyzed retrospectively. Results From a cohort of 34 patients with congenital muscular dystrophy, 12 patients from 10 families were diagnosed with muscle-eye-brain disease. The mean age of the patients was 9 ± 5.5 years (2-19 years). Mean serum creatine kinase value was 2485.80 ± 1308.54 IU/L (700-4267 IU/L). All patients presented with muscular hypotonia at birth followed by varying degrees of spasticity and exaggerated deep tendon reflexes in later stages of life. Three patients were able to walk. The most common ophthalmologic and radiologic abnormalities were cataracts, retinal detachment, periventricular white matter abnormalities, ventriculomegaly, pontocerebellar hypoplasia, and multiple cerebellar cysts. All of the patients had mutations in the POMGNT1 gene. The most common mutation detected in 66% of patients was c.1814 G > A (p.R605H). Two novel mutations were identified. Conclusions We suggest that muscle-eye-brain disease is a relatively common muscular dystrophy in Turkey. It should be suspected in patients with muscular hypotonia, increased creatine kinase, and structural eye and brain abnormalities. The c.1814 G > A mutation in exon 21 of the POMGNT1 gene is apparently a common mutation in the Turkish population. Individuals with this mutation show classical features of muscle-eye-brain disease, but others may exhibit a milder phenotype and retain the ability to walk independently. Congenital muscular dystrophy patients from Turkey carrying the clinical and radiologic features of muscle-eye-brain disease should be evaluated for mutations in POMGNT1 gene.
Polymicrogyria and lissencephaly are causally heterogeneous disorders of cortical brain development, with distinct neuropathological and neuroimaging patterns. They can be associated with additional ...structural cerebral anomalies, and recurrent phenotypic patterns have led to identification of recognizable syndromes. The lissencephalies are usually single-gene disorders affecting neuronal migration during cerebral cortical development. Polymicrogyria has been associated with genetic and environmental causes and is considered a malformation secondary to abnormal post-migrational development. However, the aetiology in many individuals with these cortical malformations is still unknown. During the past few years, mutations in a number of neuron-specific α- and β-tubulin genes have been identified in both lissencephaly and polymicrogyria, usually associated with additional cerebral anomalies including callosal hypoplasia or agenesis, abnormal basal ganglia and cerebellar hypoplasia. The tubulin proteins form heterodimers that incorporate into microtubules, cytoskeletal structures essential for cell motility and function. In this study, we sequenced the TUBB2B and TUBA1A coding regions in 47 patients with a diagnosis of polymicrogyria and five with an atypical lissencephaly on neuroimaging. We identified four β-tubulin and two α-tubulin mutations in patients with a spectrum of cortical and extra-cortical anomalies. Dysmorphic basal ganglia with an abnormal internal capsule were the most consistent feature. One of the patients with a TUBB2B mutation had a lissencephalic phenotype, similar to that previously associated with a TUBA1A mutation. The remainder had a polymicrogyria-like cortical dysplasia, but the grey matter malformation was not typical of that seen in 'classical' polymicrogyria. We propose that the cortical malformations associated with these genes represent a recognizable tubulinopathy-associated spectrum that ranges from lissencephalic to polymicrogyric cortical dysplasias, suggesting shared pathogenic mechanisms in terms of microtubular function and interaction with microtubule-associated proteins.
The aim of this study is to investigate the ecological footprint awareness levels of classroom teacher candidates. Survey model have been used in this research. The study group consists of 349 ...prospective teachers who were studying in the first, second, third and fourth grade levels of Kastamonu University Faculty of Education classroom education undergraduate program in the spring term of 2018-2019 academic year. Ecological Footprint Awareness Scale was used as data gathering tool. In the analysis of the data, t-test for independent groups and one-way ANOVA were used for multiple comparisons. For the findings of research, ecological footprint awareness of teacher candidates were examined in terms of gender, class level and settlements variables. When the results obtained from this study were examined in general, it was determined that female teacher candidates had higher ecological footprint awareness than male teacher candidates. In addition, it was observed that pre-service teachers in the fourth grade had higher ecological footprint awareness than pre-service teachers who were at the other grade levels. However, it has been found that the pre-service teachers, who have been living in the city, have higher ecological footprint awareness than the pre-service teachers, who have been living in the village.
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