PI4K2A deficiency causes innate error in intracellular trafficking with developmental and epileptic-dyskinetic encephalopathy.

OBJECTIVE: Intracellular signaling networks rely on proper membrane organization to control an array of cellular processes such as metabolism, proliferation, apoptosis, and macroautophagy in eukaryotic cells and organisms. Phosphatidylinositol 4-phosphate (PI4P) emerged as an essential regulatory lipid within organelle membranes that defines their lipid composition and signaling properties. PI4P is generated by four distinct phosphatidylinositol 4-kinases (PI4K) in mammalian cells: PI4KA, PI4KB, PI4K2A, PI4K2B. Animal models and human genetic studies suggest vital roles of PI4K enzymes in development and function of various organs, including the nervous system. Bi-allelic variants in PI4KA were recently associated with neurodevelopmental disorders (NDD), brain malformations, leukodystrophy, primary immunodeficiency, and inflammatory bowel disease. Here, we describe patients from two unrelated consanguineous families with PI4K2A deficiency and functionally explored the pathogenic mechanism. METHODS: Two patients with PI4K2A deficiency were identified by exome sequencing, presenting with developmental and epileptic-dyskinetic encephalopathy. Neuroimaging showed corpus callosum dysgenesis, diffuse white matter volume loss, and hypoplastic vermis. In addition to NDD, we observed recurrent infections and death at toddler age. We further explored identified variants with cellular assays. RESULTS: This clinical presentation overlaps with what was previously reported in two affected siblings with homozygous nonsense PI4K2A variant. Cellular studies analyzing these human variants confirmed their deleterious effect on PI4K2A activity and, together with the central role of PI4K2A in Rab7-associated vesicular trafficking, establish a link between late endosome-lysosome defects and NDD. INTERPRETATION: Our study establishes the genotype-phenotype spectrum of PI4K-associated NDD and highlights several commonalities with other innate errors of intracellular trafficking

TTC5 syndrome: Clinical and molecular spectrum of a severe and recognizable condition.

Biallelic mutations in the TTC5 gene have been associated with autosomal recessive intellectual disability (ARID) and subsequently with an ID syndrome including severe speech impairment, cerebral atrophy, and hypotonia as clinical cornerstones. A TTC5 role in IDs has been proposed based on the physical interaction of TTC5 with p300, and possibly reducing p300 co-activator complex activity, similarly to what was observed in Menke-Hennekam 1 and 2 patients (MKHK1 and 2) carrying, respectively, mutations in exon 30 and 31 of CREBBP and EP300, which code for the TTC5-binding region. Recently, TTC5-related brain malformation has been linked to tubulinopathies due to the function of TTC5 in tubulins' dynamics. We reported seven new patients with novel or recurrent TTC5 variants. The deep characterization of the molecular and phenotypic spectrum confirmed TTC5-related disorder as a recognizable, very severe neurodevelopmental syndrome. In addition, other relevant clinical aspects, including a severe pre- and postnatal growth retardation, cryptorchidism, and epilepsy, have emerged from the reversal phenotype approach and the review of already published TTC5 cases. Microcephaly and facial dysmorphism resulted in being less variable than that documented before. The TTC5 clinical features have been compared with MKHK1 published cases in the hypothesis that clinical overlap in some characteristics of the two conditions was related to the common p300 molecular pathway

The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders.

In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated to torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with TOR1A-AMC5 have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with fetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71% with higher mortality in males. Death occurred at a median age of 1.2 months (1 week - 9 years) due to respiratory failure, cardiac arrest, or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival

Half a century of amyloids: past, present and future

Amyloid diseases are global epidemics with profound health, social and economic implications and yet remain without a cure. This dire situation calls for research into the origin and pathological manifestations of amyloidosis to stimulate continued development of new therapeutics. In basic science and engineering, the cross-ß architecture has been a constant thread underlying the structural characteristics of pathological and functional amyloids, and realizing that amyloid structures can be both pathological and functional in nature has fuelled innovations in artificial amyloids, whose use today ranges from water purification to 3D printing. At the conclusion of a half century since Eanes and Glenner's seminal study of amyloids in humans, this review commemorates the occasion by documenting the major milestones in amyloid research to date, from the perspectives of structural biology, biophysics, medicine, microbiology, engineering and nanotechnology. We also discuss new challenges and opportunities to drive this interdisciplinary field moving forward. This journal i

The Role of Vitamin D Supplementation in Cystic Fibrosis: A Systematic Review

Cystic fibrosis (CF) is the most common genetic respiratory disease in the west, which is due to a malfunction in protein of cystic fibrosis transmembrane regulator (CFTR). Since some studies showed the effect of vitamin D supplementation and increment in 25OHD serum level in these patients, this study aimed to conduct a review in this scope. For reaching the available studies, a search was conducted on the studies published between2009 to 2014 in English language with the key words of vitamin D deficiency, 25OHD serum level, vitamin D supplementation and relationship with cystic fibrosis in PubMed and Google Scholar databases. In Most studies conducted on the effect of vitamin D supplementation on 25OHD serum level, an increment in 25OHD serum level was observed, though it did not reach the therapeutic target level (> 75 nmol / l or> 30 ng / ml). As a matter of fact, few studies reached the therapeutic targets. Therefore, supplementation with vitamin D in patients with CF may assist to increase the level of serum 25OHD, though achieving appropriate levels of serum 25OHD depends on conducting more studies

Association between Eating Disorder and Depression among Medical Students of Islamic Azad university of Yazd in 2013

Introduction: Eating disorder is one of the most prevalent psychiatric disorders that cause various problems for physical health, psychological functioning and quality of life. The purpose of this study was to evaluate and determine the association between eating disorder and depression among medical students of Free University of Yazd, Iran in 2013. Methods: In a descriptive study, a total of 400 medical students were selected via convenient sampling. Students were assessed by 2 questionnaires: Eat-26 and Beck. The data was analyzed using chi square, fisher exact and ANOVA tests. Results: According to the results,7/5% of students suffered from eating disorder , 25/8% from moderate, and 22% from severe depression. The relative frequency of eating among the participants according to age, gender, state of residence, and marital status were identical. However there was a significant correlation between the relative prevalence of eating disorder and depression severity among the medical students. Conclusion: The findings of the present study imply that eating disorder had a significant association with severity of depression. Thus, educating of medical students by consulting centers can be effective for early diagnosis and treatment

Effect of Vitamin D Supplementation on Anthropometric Parameters in Patients With Metabolic Syndrome

Introduction: Obesity has become epidemic worldwide and is now a great public and clinical health challenge. Metabolic syndrome is one of the disorders associated with obesity. Accumulating evidence shows inverse correlation of serum 25(OH)D3 with obesity and anthropometric parameters. The aim of the present study was to investigate the effect of vitamin D supplementation on anthropometric parameters in patients with metabolic syndrome. Methods:We utilized randomized controlled double – blind intervention, administering 300,000 IU vitamin D in divided doses of 6 50,000 IU pearls per day to the treatment group and 6 pearls of placebo to control group in the first week of intervention. Participants were 88 men and women aged 30 to 65 which had metabolic syndrome according to NCEP-ATP III definition and had referred to diabetes clinic of Emam Khomeini Hospital in Tehran. 25(OH)D3 levels and anthropometric parameters including weight, BMI, waist circumference and waist to hip ratio were measured at the beginning and 3 months later. Results: There was a significant increase in serum 25(OH)D3 levels from 20 ng/ml to 33 ng/ml at the end of the study in vitamin D supplemented group (P-value < 0.001). There was a significant decrease in waist circumference in the vitamin D supplemented group at the end of the study (P-value = 0.005). There was no significant difference in weight, BMI and waist to hip ratio in the groups at the end of the study. Conclusion: Improving vitamin D status decreases waist circumference but does not affect other anthropometric parameters in patients with metabolic syndrome

The Effect of Apple Vinegar on Lipid Profiles and Anthropometric Indices in Type 2 Diabetes Patients with Dyslipidemia: A Randomized Clinical Trial

Introduction: Type 2 diabetes is regarded as the most common and the most important metabolic disease which is progressively increasing in different societies. In this study, the effect of apple vinegar on lipid profiles and anthropometric indices was examined in Type 2 diabetes patients with dyslipidemia. Methods: Sixty-two Type 2 diabetic patients with dyslipidemia were randomly assigned into a control (n=30) and an experimental group(n=32). The experimental group was instructed to use 10 cc of apple vinegar soluble in a glass of water two times a day 1 hr before each meal for 8 weeks. Results: The participants’ serum lipid profiles( Cholesterol, TG,LDL and HDL) and also anthropometric indices(Weight, Height and Waist Circumference) were measured before and after the intervention. Finally, in spite of a reducing trend in cholesterol and LDL in apple vinegar group, no significant differences were observed between the two groups (pvalue>0/05). Conclusion: The present study revealed that consuming 20 cc of apple vinegar daily had no effect on serum lipoprotein profiles and anthropometric indices in Type 2 diabetes patients with dyslipidemia

The relationship between sodium intake and some bone minerals and osteoporosis risk assessment instrument in postmenopausal women

Background: The results of the studies on the effects of sodium on bone metabolism have been inconsistent. There is no definitive answer to the question of whether sodium restriction can be associated with a lower incidence of osteoporosis. What reinforces the necessity of designing this study is the lack of findings with the approach of examining the effects of sodium on bone in our country. Methods: This was a cross-sectional study conducted on 185 retired female teachers aged 45 to 70. Sodium intake was evaluated using two methods: A 24-hour recall and a 12-hour urine sample. To assess bone health, ORAI index was calculated for each individual. Urinary calcium, phosphorus, potassium and serum vitamin D and PTH were measured as laboratory variables. To compare the general characteristics of the participants across tertiles of urinary sodium, the analysis of variance (ANOVA) was used for quantitative variables and the Chi-square test for categorical variables. Results: Phosphorous, calcium and potassium urinary excretion rate increased with the increase in urinary sodium (p < 0.05). However, the changes in serum vitamin D, and PTH levels across tertiles of urinary sodium were not significant. Changes in urinary sodium levels were not significant (p=0.933) in ORAI groups (sorted by rating). The relationship between urinary calcium and sodium was apparent in low calcium intake (r=0.415, p < 0.001), but not in higher calcium intake (r=0.144, p=0.177). Conclusion: Although urinary calcium and potassium increased with the increase in sodium intake, no relationship was found between sodium and ORAI

Food Security Status of Elders and Its Related Factors in Arak in 2012

Abstract Introduction: Today, increased life expectancy, reduced mortality rates, and improved health conditions caused to an increase in number of elderly people, as one of the vulnerable groups in the society. On the other hand, food security is one of the necessary prerequisites for the health of the elderly people. Therefore, the present study intended to investigate the food security status of the elderly people as well as its related factors. Methods: This descriptive cross-sectional study was conducted in 2012 consisting of 300 elderly people of Arak city. The study data were collected through FaCPS-FSSM food security questionnaire validated for the elderly via conducting interviews. In order to analyze the study data, SPSS software was utilized applying Chi square test, independent t&ndash;test, Pearson's correlation and regression. Results: The results of the present study revealed that 39.3% of the elderly people had a full food security, 29 % reported food insecurity without hunger, 20.7% showed moderate food insecurity and 11% had severe food insecurity. Moreover, a significant relationship was detected between education level, occupation, marital status, body mass index, disease and household dimension with the food security (p <%5). Conclusions: Considering that close to 60.7% of the studied elderly revealed some degree of food insecurity as well as the various factors significantly associated with this problem in the present study, this problem in this level of vulnerable population demonds to be attended more than ever