Measurement of the Neutrophils Count and Oxidative Burst in Neutrophils of Patients with Sanjad Sakati Syndrome.

Sanjad Sakati Syndrome (SSS) is categorized as a neuroendocrine-related disease due to disorders of the nervous and hormonal systems. Since hormonal changes in these patients may affect the nature and function of the immune system. Thus, in this study, cell count and phagocytotic function of neutrophils were evaluated which may be influenced by changes in the hormonal rate and growth factors. In this study, the neutrophil count value and the oxidative burst were evaluated in six patients diagnosed with SSS and six healthy individuals. There was a significant reduction in the neutrophil count observed in SSS patients compared to healthy controls (37.41±7.93 percent vs. 66.5±6.8 percent). However, there was no significant difference in neutrophil oxidative index between patients with SSS and control subjects (172.33±55.08 vs. 217.00±77.38). We concluded that in patients with SSS, the phagocytic activity of neutrophils was not affected by hormonal changes, while the number of neutrophils and neutrophil-to-lymphocyte ratio (NLR) index were decreased.

Genetic features of patients with MPS type IIIB: Description of five pathogenic gene variations.

BACKGROUND: There are four distinct forms of Sanfilippo syndrome (MPS type III), each of which is an autosomal lysosomal storage disorder. These forms are caused by abnormalities in one of four lysosomal enzymes. This study aimed to identify possible genetic variants that contribute to Sanfilippo IIIB in 14 independent families in Southwest Iran. METHODS: Patients were included if their clinical features and enzyme assay results were suggestive. The patients were subsequently subjected to Sanger Sequencing to screen for Sanfilippo-related genes. Additional investigations have been conducted using various computational analyses to determine the probable functional effects of diagnosed variants. RESULTS: Five distinct variations were identified in the NAGLU gene. This included two novel variants in two distinct families and three previously reported variants in 12 distinct families. All of these variations were recognized as pathogenic using the MutationTaster web server. In silico analysis showed that all detected variants affected protein structural stability; four destabilized protein structures, and the fifth variation had the opposite effect. CONCLUSION: In this study, two novel variations in the NAGLU gene were identified. The results of this study positively contribute to the mutation diversity of the NAGLU gene. To identify new disease biomarkers and therapeutic targets, precision medicine must precisely characterize and account for genetic variations. New harmful gene variants are valuable for updating gene databases concerning Sanfilippo disease variations and NGS gene panels. This may also improve genetic counselling for rapid risk examinations and disease surveillance.

Identification of new variants in patients with mucopolysaccharidosis in consanguineous Iranian families.

Introduction: Mucopolysaccharidoses are a group of lysosomal storage disorders that include seven types that are classified based on the enzymes that are disrupted. Malfunction of these enzymes leads to the accumulation of glycosaminoglycans (GAGs) in various tissues. Due to genetic and clinical heterogeneity, diagnosing and distinguishing the different types is challenging. Genetic methods such as whole exome sequencing (WES) and Sanger sequencing are accurate methods for detecting pathogenic variants in patients. Methods: Thirty-two cases of mucopolysaccharidosis, predominantly from families with consanguineous marriages, were genetically examined. Out of these, fourteen cases underwent targeted sequencing, while the rest underwent WES. The results of WES were analyzed and the pathogenicity of the variants was examined using bioinformatics tools. In addition, a segregation analysis within families was carried out. Results: In most cases, a pathogenic or likely pathogenic variant was detected. Sixteen previously reported variants and six new variants were detected in the known IDS (c.458G>C, c.701del, c.920T>G), GNS (c.1430A>T), GALNS (c.1218_1221dup), and SGSH (c.149T>C) genes. Furthermore, we discovered a c.259G>C substitution in the NAGLU gene for the first time in three homozygous patients. This substitution was previously reported as heterozygous. Except for the variants related to the IDS gene, which were hemizygous, all the other variants were homozygous. Discussion: It appears that the high rate of consanguineous marriages in the families being studied has had a significant impact on the occurrence of this disease. Overall, these findings could expand the spectrum of pathogenic variants in mucopolysaccharidoses. Genetic methods, especially WES, are very accurate and can be used alone or in conjunction with other diagnostic methods for a more precise and rapid diagnosis of mucopolysaccharidoses. Additionally, they could be beneficial for family screening and disease prevention.

Inborn Errors of Metabolism Associated With Autism Among Children: A Multicenter Study from Iran.

OBJECTIVE: This study aimed to find the common inborn errors of metabolism in Iranian patients with autism spectrum disorder. METHODS: In this cross-sectional multicenter study, 105 children and adolescents with autism spectrum disorder from six centers in different cities of Iran were enrolled between August, 2019 and October, 2020. Metabolic screening, including measuring plasma levels of amino acids, acylcarnitines, creatine, and guani-dinoacetate, and urinary levels of organic acids, purines, and pyrimidines was performed. Other data, including age, parental consanguinity, history of seizure, developmental mile-stones, and physical examination, were also recorded. RESULTS: An inborn error of metabolism was found in 13 (12.4%) patients. Five patients (4.8%) had cerebral creatine deficiency syndrome, 4 (3.8%) had arginine succinate aciduria, 2- methylbutyryl glycinuria, short-chain acyl-CoA dehydrogenase deficiency, and combined methylmalonic aciduria/malonic aciduria. There was a strong association between positive meta-bolic evaluation and parental consanguinity, history of seizures, microcephaly, and delayed development. CONCLUSIONS: Our results suggest that metabolic screening should be performed in the cases of autism associated with parental consanguinity, developmental delay, and a history of seizures. The assays to be considered as a screening panel include plasma or blood amino acids, acylcarnitines, creatine and guanidinoacetate, and urinary levels of organic acids.

Association of vitamin D status with COVID-19 disease severity in pediatric patients: A retrospective observational study.

Background and Aims: Vitamin D deficiency is associated with increased vulnerability to respiratory infections. This study aimed to determine the potential relationships between coronavirus disease 2019 (COVID-19) severity, serum vitamin D concentrations, and some inflammatory markers among pediatric COVID-19 patients in Iran. Methods: A retrospective study was conducted among hospitalized pediatric COVID-19 cases in Abuzar Hospital (Ahvaz, Iran) for 6 months. The COVID-19 diagnosis was based on the real-time reverse transcription-polymerase chain reaction technique. Demographic and clinical data of patients were recorded. Patients with serum vitamin D levels lower than 20 ng/ml were assigned as Group 1 and those with serum vitamin D concentrations equal to or more than 20 ng/ml were considered as Group 2. Results: A total of 144 patients were enrolled. Their mean age was 80 ± 49 months (range: 1-16 years). Patients in Group 1 had significantly lower levels of serum vitamin D, calcium, and lymphocytes, as well as higher fibrinogen, d-dimer, and C-reactive protein (CRP) levels compared with those in Group 2 (p < 0.001). In addition, they had a significantly higher dry cough, fever, chest radiographic findings, respiratory rate, and longer hospital length of stay than patients in Group 2. Serum concentrations of vitamin D were positively correlated with levels of serum calcium, lymphocytes, and neutrophils but negatively correlated with CRP, fibrinogen, and d-dimer values. Furthermore, patients with moderate or severe courses of COVID-19 had significantly higher inflammatory markers (CRP, d-dimer, and fibrinogen), as well as lower levels of serum calcium, vitamin D, lymphocytes, and neutrophils than those with mild COVID-19 (p < 0.001). In the multivariate analysis, fibrinogen level on admission was detected as the independent predictor of severe COVD-19 (odds ratio = 1.06, 95% confidence interval: 1.03-1.09; p < 0.001). Conclusion: This study indicated associations between the severity of COVID-19, serum vitamin D concentrations, and some inflammatory markers in pediatric COVID-19 patients.

Molecular characterization of a large cohort of mucopolysaccharidosis patients: Iran Mucopolysaccharidosis RE-diagnosis study (IMPRESsion).

Mucopolysaccharidoses (MPSs) are rare, heterogeneous inborn errors of metabolism (IEM) diagnosed through a combination of clinical, biochemical, and genetic investigations. The aim of this study was molecular characterization of the largest cohort of Iranian MPS patients (302 patients from 289 unrelated families), along with tracking their ethnicity and geographical origins. 185/289 patients were studied using an IEM-targeted NGS panel followed by complementary Sanger sequencing, which led to the diagnosis of 154 MPS patients and 5 non-MPS IEMs (diagnostic yield: 85.9%). Furthermore, 106/289 patients who were referred with positive findings went through reanalysis and confirmatory tests which confirmed MPS diagnosis in 104. Among the total of 258 MPS patients, 225 were homozygous, 90 harbored novel variants, and 9 had copy number variations. MPS IV was the most common type (34.8%) followed by MPS I (22.7%) and MPS VI (22.5%). Geographical origin analysis unveiled a pattern of distribution for frequent variants in ARSB (c.430G>A, c.962T>C [p.Leu321Pro], c.281C>A [p.Ser94*]), GALNS (c.319G>A [p.Ala107Thr], c.860C>T [p.Ser287Leu], c.1042A>G [p.Thr348Ala]), and IDUA (c.1A>C [p.Met1Leu], c.1598C>G [p.Pro533Arg], c.1562_1563insC [p.Gly522Argfs*50]). Our extensive patient cohort reveals the genetic and geographic landscape of MPS in Iran, which provides insight into genetic epidemiology of MPS and can facilitate a more cost-effective, time-efficient diagnostic approach based on the region-specific variants.

Molecular diagnosis of maturity onset diabetes of the young in Iranian patients: improving management.

BACKGROUND: The purpose of this study is to identify the mutations of the most common form of maturity-onset diabetes of the young (MODY), also known as MODY3, in diabetic patients suspected of MODY. This can recommend appropriate medical surveillance of at-risk family members of MODY based on the genetic cause. METHODS: We analyzed the clinical course of 19 patients from 12 unrelated Iranian families with diabetes features. The coding regions and intron-exon boundaries of the hepatocyte nuclear factor 1 alpha (HNF1A) gene were studied by polymerase chain reaction (PCR) and sanger sequencing. Also, the detected mutation was analyzed by bioinformatics tools. RESULTS: One novel frameshift insertion mutation (p.Glu11Argfs*12) was detected in one of the probands and seven other patients of her family with the heterozygote state. The mutation is located in the exon1 of the dimerization domain of the HNF1A gene. According to the In Silico analysis, the detected mutation is predicted as a pathogenic one. CONCLUSIONS: Differential diagnosis between MODY3 and other forms of diabetes can be considered a necessity in terms of overlapping symptoms of MODY3 with type1 or 2 diabetes. Molecular genetic testing can provide an accurate diagnosis for optimal management.

Changes in body mass index after pediatric renal transplantation.

Significant weight gain following renal transplantation is common in adult and pediatric recipients and mostly depends on receiving higher doses of steroids, changes in mood and feelings, as well as their level of physical activities. This study was performed to evaluate body weight and body mass index (BMI) before and after kidney transplantation in children and adolescents. In this cross-sectional study, 71 pediatric renal transplant recipients (42 boys and 29 girls) were included. World Health Organization criteria were used for comparing Z-score BMI for age in our cases. Overweight was defined as Z-score BMI >+1 SD (standard deviation) and obesity as >+2 SD. At the time of transplantation, the mean age was 10.8 ± 3 years (5-16 years) and based on BMIZ-score, the patients were found to be thin (BMIZs <-2 SD) in 16.9%, normal (BMIZs = -2 to +1 SD) in 67.6%, overweight (>+1 SD to +2 SD) in 9.9%, and obese (BMIZs >+2 SD) in 5.6%.The mean follow-up duration after transplantation was 3.57 ± 1.68 years (1-7 years) and at the time of reevaluation after transplant, their mean age was 14.4 years (6-18 years). The mean BMI was 22 ± 5.3 kg/m2, and for BMI grouping, the patients were thin in 7%, normal in 54.9%, overweight in 21.1%, and obese in 17%. Pretransplant thinness (BMIZs <-2 SD) was found in 12 patients (16.9%), equally in boys and girls, and in most of them (83.3%), BMIZs changed to normal or even >+1 SD after transplant. Chronic continuous decrease of glomerular filtration rate (CCD/GFR) was found in 27 cases (38%); 74.1% were male (P = 0.045), hypertriglyceridemia was found in 74.1% (P = 0.023%), hypercholesterolemia in 63% (P = 0.032),and obesity in 18.5% (p = 0.5). The incidence of obesity has tripled after kidney transplantation. It was not a risk factor for graft or patient survival in our experience, whereas pretransplant obesity had some effects on long-term graft outcome.

The Effects of Synbiotic Supplementation on Glycemic Status, Lipid Profile, and Biomarkers of Oxidative Stress in Type 1 Diabetic Patients. A Placebo-Controlled, Double-Blind, Randomized Clinical Trial.

BACKGROUND AND OBJECTIVE: The aim of the present study was to evaluate the effects of synbiotic on glycemic status, lipid profile, and biomarkers of oxidative stress in type 1 diabetes mellitus (T1DM) patients. MATERIALS AND METHODS: In this double-blind clinical trial, 50 T1DM patients were randomly allocated to intervention (n = 25) and control (n = 25) groups and received either synbiotic powder (Lactobacillus sporogenes GBI-30 (probiotic), maltodextrin and fructooligosaccharide (prebiotic)) or placebo 2 g per day for 8 weeks. Fasting blood samples were collected before and after the intervention to measure fasting blood glucose (FBG), insulin concentration, hemoglobin A1c (HbA1c), lipid profile, and biomarkers of oxidative stress such as total antioxidant capacity (TAC) and hs-C-reactive protein (hs-CRP). RESULTS: Supplementation with synbiotic resulted in a significant decrease in the mean serum levels of HbA1c and hs-CRP (p = 0.01 and p = 0.004, respectively), and marginally significant decrease in FBG (p = 0.05) in the intervention group post- intervention. Also, the mean changes of FBG and hs-CRP were significantly lower in the intervention group compared with the control group (p = 0.03 and p = 0.005, respectively). There were no significant changes found in lipid profile in intervention group post-intervention (p≥ 0.05). The mean serum levels of insulin and TAC were significantly increased in the intervention group post-intervention (p = 0.001). There was a significant increase in the mean changes of TAC (p = 0.005) in the intervention group compared with the control group. CONCLUSION: The 8-week synbiotic supplementation in T1DM patients may be effective in improvement of FBG, HbA1c, insulin, hs-CRP, and TAC.

Effect of prednisolone on linear growth in children with nephrotic syndrome / Efeito da prednisolona sobre o crescimento linear em crianças com síndromenefrótica

Abstract Objective This study aims at determining the relationship between prednisolone cumulative dose and linear growth in pre-pubertal children with idiopathic nephrotic syndrome. Method This cross-sectional study was conducted on all children with idiopathic nephrotic syndrome registered to the pediatric nephrology department at the main referral children's hospital in Southwestern Iran. Inclusion criteria included age (males <12 years; females <10 years), >6 months of use, and the minimum prednisolone cumulative dose of 152 mg/kg. The exclusion criteria were individuals who had entered puberty or had other diseases affecting linear growth. Based on the prednisolone cumulative dose of ≥550 mg/kg (four or more relapses), the children were divided into two groups. All data regarding age, height, and weight at disease onset and the last visit, bone age, and the parents' height were collected. Secondary variables including mid-parental target height and predicted adult height were also calculated. Height data were compared between the different rates of relapse. Results A total of 97 children (68% male) were enrolled. Their post-treatment mean height Z-score was less than that obtained before treatment (−0.584 vs. −0.158; p = 0.001). Subjects with higher prednisolone cumulative doses were found to have more reduction in height Z-score (p = 0.001). Post-treatment height prediction also showed less growth potential compared to pre-treatment target height (p = 0.006). Thirty-three children (34.4%) had four or more relapses, among whom more mean-height Z-score decreases were found compared to those with less-frequent relapses (−0.84 vs. −0.28; p = 0.04). Conclusion This study showed the negative effect of cumulative dosages of prednisolone on linear growth, which was greater in children with four or more relapses.

Resumo Objetivo Determinar a relação entre a dose cumulativa de prednisolona e o crescimento linear em crianças pré-púberes com síndrome nefrótica idiopática. Método Estudo transversal conduzido em todas as crianças com síndrome nefrótica idiopática registradas no departamento de nefrologia pediátrica no principal hospital infantil para encaminhamento no sudoeste do Irã. Os critérios de inclusão incluíram idade (meninos < 12 anos; meninas < 10 anos), > 6 meses e a dose cumulativa de prednisolona mínima de 152 mg/kg. Os critérios de exclusão foram indivíduos que entraram na puberdade ou tinham outras doenças que afetam o crescimento linear. Com base na dose cumulativa de prednisolona de ≥ 550 mg/kg (≥ 4 recidivas), as crianças foram divididas em dois grupos. Foram coletados todos os dados relacionados a idade, estatura e peso no início da doença e na última visita, idade óssea e estatura dos pais. Também foram calculadas as variáveis secundárias, inclusive estatura-alvo e estatura adulta prevista. Os dados de estatura foram comparados entre as diferentes taxas de recidivas. Resultados Foram inscritas 97 crianças (68% do sexo masculino). Seu escore z de estatura média pós-tratamento foi inferior ao obtido antes do tratamento (−0,584 em comparação com −0,158; p = 0,001). Os indivíduos com maiores doses cumulativas de prednisolona mostraram maior redução no escore z para estatura (p = 0,001). A estatura pós-tratamento também foi preditiva de menor potencial de crescimento em comparação com a estatura-alvo pré-tratamento (p = 0,006); 33 crianças (34,4%) apresentaram ≥ 4 recidivas, entre as quais foram encontradas mais reduções médias no escore z para estatura em comparação com as recidivas menos frequentes (−0,84 em comparação com −0,28; p = 0,04). Conclusão Este estudo mostrou o efeito negativo das doses cumulativas de prednisolona sobre o crescimento linear, que foi maior em crianças com ≥ 4 recidivas.

Clinical features and tubulin folding cofactor E gene analysis in Iranian patients with Sanjad-Sakati syndrome / Características clínicas e análise genética e de cofatores de dobramento da tubulinaem pacientes iranianos com síndrome de Sanjad-Sakati

Abstract Objective Permanent hypoparathyroidism can be presented as part of genetic disorders such as Sanjad-Sakati syndrome (also known as hypoparathyroidism—intellectual disability-dysmorphism), which is a rare autosomal recessive disorder. Our aim was to confirm the diagnosis of a group of patients with dysmorphism, poor growth, and hypoparathyroidism clinically labeled as Sanjad-Sakati syndrome and to identify for the first time the genetic variations on Iranian patients with the same ethnic origin. Methods In this study, 29 cases from 23 unrelated Arab kindreds with permanent hypoparathyroidism and dysmorphism indicating Sanjad-Sakati syndrome were enrolled for 10 years in the southwest of Iran. The mutational analysis by direct sequencing of the tubulin folding cofactor E gene was performed for the patients and their families, as well as their fetuses using genomic DNA. Results Twenty-eight out of 29 cases had parental consanguinity. Twenty-seven cases presented with hypocalcemia seizure and two were referred because of poor weight gain and were found to have asymptomatic hypocalcemia. The dysmorphic features, hypocalcemia in the setting of low to normal parathyroid hormone levels and high phosphorus led to the diagnosis of these cases. Sequencing analysis of the tubulin folding cofactor E gene revealed a homozygous 12-bp deletion (c.155-166del) for all patients. Following that, prenatal diagnosis was performed for eight families, and two fetuses with a homozygous 12-bp deletion were identified. Conclusion These results make it much easier and faster to diagnose this syndrome from other similar dysmorphisms and also help to detect carriers, as well as prenatal diagnosis of Sanjad-Sakati syndrome in high-risk families in this population.

Resumo Objetivo O hipoparatireoidismo permanente pode estar presente como parte das doenças genéticas como na síndrome de Sanjad-Sakati (também chamada de síndrome de hipoparatireoidismo, retardo e dismorfismo), que é um distúrbio autossômico recessivo raro. Nosso objetivo foi confirmar o diagnóstico de um grupo de pacientes com dismorfismo, crescimento deficiente e hipoparatireoidismo clinicamente identificado como síndrome de Sanjad-Sakati e identificar as variações genéticas, pela primeira vez, em pacientes iranianos com a mesma origem étnica. Métodos Neste estudo, foram inscritos 29 casos de 23 famílias árabes sem parentesco com hipoparatireoidismo e dismorfismo indicando síndrome de Sanjad-Sakati, durante 10 anos no sudoeste do Irã. Foi feita a análise mutacional por sequenciamento direto do gene do cofator E de dobramento da tubulina dos pacientes e de suas famílias e também de seus fetos com o DNA genômico. Resultados Apresentaram consanguinidade parental 28 dos 29 casos. Desses, 27 casos apresentaram convulsão por hipocalcemia e dois foram encaminhados devido ao baixo ganho de peso, considerando diagnóstico de hipocalcemia assintomática. As características dismórficas, hipocalcemia na configuração de níveis de hormônio da paratireoide baixos a normais e alto nível de fósforo levaram ao diagnóstico dos casos. A análise de sequenciamento do gene do cofator E de dobramento da tubulina revelou deleção homozigótica de 12 pares de base (pb) (c.155-166del) em todos os pacientes. Após isso, foi feito o diagnóstico pré-natal em oito famílias e dois fetos foram identificados com deleção homozigótica de 12 pb. Conclusão Esses resultados tornam o diagnóstico dessa síndrome muito mais fácil e rápido do que outros dismorfismos semelhantes e também ajudam a detectar portadores, bem como o diagnóstico pré-natal da síndrome de Sanjad-Sakati em famílias de alto risco nessa população.

Effect of prednisolone on linear growth in children with nephrotic syndrome.

OBJECTIVE: This study aims at determining the relationship between prednisolone cumulative dose and linear growth in pre-pubertal children with idiopathic nephrotic syndrome. METHOD: This cross-sectional study was conducted on all children with idiopathic nephrotic syndrome registered to the pediatric nephrology department at the main referral children's hospital in Southwestern Iran. Inclusion criteria included age (males <12 years; females <10 years), >6 months of use, and the minimum prednisolone cumulative dose of 152mg/kg. The exclusion criteria were individuals who had entered puberty or had other diseases affecting linear growth. Based on the prednisolone cumulative dose of ≥550mg/kg (four or more relapses), the children were divided into two groups. All data regarding age, height, and weight at disease onset and the last visit, bone age, and the parents' height were collected. Secondary variables including mid-parental target height and predicted adult height were also calculated. Height data were compared between the different rates of relapse. RESULTS: A total of 97 children (68% male) were enrolled. Their post-treatment mean height Z-score was less than that obtained before treatment (-0.584 vs. -0.158; p=0.001). Subjects with higher prednisolone cumulative doses were found to have more reduction in height Z-score (p=0.001). Post-treatment height prediction also showed less growth potential compared to pre-treatment target height (p=0.006). Thirty-three children (34.4%) had four or more relapses, among whom more mean-height Z-score decreases were found compared to those with less-frequent relapses (-0.84 vs. -0.28; p=0.04). CONCLUSION: This study showed the negative effect of cumulative dosages of prednisolone on linear growth, which was greater in children with four or more relapses.

Clinical features and tubulin folding cofactor E gene analysis in Iranian patients with Sanjad-Sakati syndrome.

OBJECTIVE: Permanent hypoparathyroidism can be presented as part of genetic disorders such as Sanjad-Sakati syndrome (also known as hypoparathyroidism-intellectual disability-dysmorphism), which is a rare autosomal recessive disorder. Our aim was to confirm the diagnosis of a group of patients with dysmorphism, poor growth, and hypoparathyroidism clinically labeled as Sanjad-Sakati syndrome and to identify for the first time the genetic variations on Iranian patients with the same ethnic origin. METHODS: In this study, 29 cases from 23 unrelated Arab kindreds with permanent hypoparathyroidism and dysmorphism indicating Sanjad-Sakati syndrome were enrolled for 10 years in the southwest of Iran. The mutational analysis by direct sequencing of the tubulin folding cofactor E gene was performed for the patients and their families, as well as their fetuses using genomic DNA. RESULTS: Twenty-eight out of 29 cases had parental consanguinity. Twenty-seven cases presented with hypocalcemia seizure and two were referred because of poor weight gain and were found to have asymptomatic hypocalcemia. The dysmorphic features, hypocalcemia in the setting of low to normal parathyroid hormone levels and high phosphorus led to the diagnosis of these cases. Sequencing analysis of the tubulin folding cofactor E gene revealed a homozygous 12-bp deletion (c.155-166del) for all patients. Following that, prenatal diagnosis was performed for eight families, and two fetuses with a homozygous 12-bp deletion were identified. CONCLUSION: These results make it much easier and faster to diagnose this syndrome from other similar dysmorphisms and also help to detect carriers, as well as prenatal diagnosis of Sanjad-Sakati syndrome in high-risk families in this population.

Niemann-Pick Diseases: The Largest Iranian Cohort with Genetic Analysis.

OBJECTIVES: Niemann-Pick diseases (NPD) is an autosomal recessive inherited lysosomal lipid storage disorder which occurs due to a defect in cellular cholesterol trafficking, leading to excess lipid accumulation in multiple organ systems such as the brain, lungs, spleen, and liver. SPMD1-associated disease includes classic infantile and visceral NPD type A and B respectively. Type C NPD is subacute or juvenile. MATERIALS & METHODS: During 2012-2016, the patients who had the clinical and biochemical signs and symptoms of different types of NPD, underwent genetic analysis. All patients were collected from five provinces in Iran (Razavi Khorasan, South Khorasan, Khozaestan, Isfahan and Tehran province). Sanger sequencing of the candidate genes for NPD was performed followed by bioinformatics analysis to confirm the types of NPD and to identify novel mutations. All patients underwent full clinical assessment. RESULTS: We present two cases with NPD type A, six cases with NPD type B, and 11 cases with type C with various enzymatic defects identified in these cases. Within these 19 patients, we present 9 previously reported mutations and 10 novel mutations causing NPD. CONCLUSION: This study is the largest Iranian study for NPD analysis ever. Our report demonstrates that NPD has a variable age of onset and can present early in life. We investigated the clinical and genetic manifestations of a large Iranian cohort. Understanding the variable presentation of NPD will allow for clinicians to have a high index of suspicion for the disease.

Identification of arylsulfatase B gene mutations and clinical presentations of Iranian patients with Mucopolysaccharidosis VI.

BACKGROUND: Mucopolysaccharidosis (MPS) type VI, also known as Maroteaux-Lamy syndrome, is an autosomal recessive lysosomal storage disorder caused by a deficiency in arylsulfatase B (ARSB) enzyme. Our objectives were to investigate clinical phenotypes and performed molecular studies in Iranian patients with MPS VI, for the first time, in the southwestern Iran. METHODS: We studied 14 cases from 10 unrelated kindreds with MPS VI that were enrolled during 8 years. The mutational analysis of coding and flanking regions of ARSB gene was performed for the patients and their families using genomic DNA from whole blood by direct sequencing. RESULTS: All cases had parental consanguinity. Except one who had Fars ethnicity and presented with a very mild degree of coarse face, but normal otherwise, even near normal height, all were from Arab ethnicity with characteristic phenotypes including severe facial changes, cardiac involvement and dysostosis multiplex. Sequencing analysis of ARSB gene revealed four pathogenic homozygote mutations, including a novel nonsense mutation c.281C>A (p.Ser94X) in 9 patients, as well as, a known nonsense mutation c.753C>G (p.Try251X) in 3 cases, and two missense mutations c.904G>A (p.Gly302Arg) and c.454C>T (p.Arg152Trp) in two cases. The type of mutations affected the severity patient's phenotypes. CONCLUSIONS: These findings increased the genetic databases of Iranian patients with MPS VI and would be so much helpful for the high-risk families to speed the detection of carriers with accuracy and perform the prenatal test of disorder with cost-effective in this population.

Childhood onset type 1 diabetes at a tertiary hospital in south-western Iran during 2000-2015: Rapid increase in admissions and high prevalence of DKA at diagnosis.

AIMS: Incidence of type 1 diabetes mellitus (T1DM) is increasing worldwide. We aimed to study trends in presentation and incidence of childhood diabetes in the last 15years in south-western Iran. METHODS: During a detailed review of compiled records of the main tertiary children's hospital of southwest of Iran, from January 2000 to December 2009, the following clinical information relevant to diabetes were analysed: admissions, demographic data, clinical and laboratory findings, hospital course, and mortality. Study continued 5years more to find out the real rate of increase. Significant findings with respect to the incidence of DKA, gender and age of subjects were summarized from among these cases. A total of 297 (known and new) cases were enrolled in the 1st (10year) stage of study and 691 new subjects in the 2nd (5year) period to check the trend in the whole 15year study period. RESULTS: In the 1st period; excluding 129 repeated admissions, 297 cases were enrolled for analysis: 223 new and 74 known cases. Among the new cases, 67.3% presented with DKA, without any gender bias. Mortality rate in DKA subjects was 4% with higher risk in the <2year group and in girls (boy: girl=1:7; p=0.039). Adding the 2nd study period (total 15years) disclosed a rapid rise of incidence (new cases/5year) as 89, 134 and 691 new diabetes cases for the 1st, 2nd and 3rd 5year period of study respectively. The final annual incidence for <15year age group in 2015 was 13.35/100000. CONCLUSIONS: The most new cases of T1DM presented with DKA, which is similar to the other developing countries. Such an increasing incidence of DM proposes more attention for periodic retraining of families and health staff to earlier diagnosis and management of new subjects, and to reduce morbidity and mortality rates.

Thyroid scintigraphy in three-year-old children with congenital hypothyroidism in correlation with neonatal TSH.

INTRODUCTION: A large number of congenital hypothyroidism (CH) cases in Iran are transient. This study was designed to investigate the aetiology of permanent CH (PCH) by thyroid scintigraphy (TS) and its relationship with the first diagnostic thyrotropin (TSH). MATERIAL AND METHODS: During 12 years (2005-2017) of CH screening in southwest Iran, all infants referred with the diagnosis of CH were followed until their third birthday, when they were re-evaluated for serum T4, TSH after discontinuing the treatment for 3-4 weeks. If the last test indicated a PCH state (TSH >10 mU/L with any levels of T4), TS was performed, and, based on the results, the patients were categorised as agenesis, dysgenesis (sublingual, thyroglossal cyst), and normal/diffuse goitre (indicating dyshormonogenesis). RESULTS: After excluding all transient CH subjects, 224 permanent CH cases were enrolled (52.7% female). Seasonal distributions were as follows: spring: 25.7%, summer: 27.9%, autumn: 20.3%, and winter: 26.1%. No significant differences were found between females and males and the different modes of delivery (55.4% were delivered by caesarean section) regarding T4, TSH (p > 0.05). Of a total of 213 performed scans, 20.7% had agenesis, 36.2% had dysgenesis, and 43.2% were normal or goitrous. Those with agenesis/dysgenetic thyroid had a lower T4 and a higher TSH than those with normal scans. However, the differences were not significant. Compared to those who had TSH < 40 mU/L, patients with TSH ≥ 40mU/L had 46% (95% CI: 1.06-2.02) more risk of agenesis or dysgenesis in TS. CONCLUSIONS: More than 40% of PCH are caused by dyshormonogenesis in Iran. Having a TSH ≥ 40 mU/L after the first week of life significantly raises the probability of thyroid agenesis/dysgenesis as the cause.

Higher prevalence of permanent congenital hypothyroidism in the Southwest of Iran mostly caused by dyshormonogenesis: a five-year follow-up study

ABSTRACT Objective: The incidence of congenital hypothyroidism (CH) varies globally. This 5-year study aimed to determine the prevalence of permanent CH in the southwest of Iran. Materials and methods: Between January 2007 and December 2009, all newborns in Ahvaz, the biggest city in the southwest of Iran, were screened for CH using a heel-prick sample for thyrotropin (TSH) levels. Subjects with TSH ≥ 5 mU/L were evaluated for T4-TSH. Infants with T4 < 6.5 µg/dL, TSH > 10 mU/L, and normal T4 but persistent (> 60 days) high TSH were considered to have CH. After the third birthday, treatment was discontinued, and T4-TSH was reevaluated; subjects with TSH ≥ 10 mU/L were investigated using thyroid Tc99 scintigraphy (TS). Based on TS, they were classified as normal, dysgenetic, or athyretic (agenesis). Results: Screening was performed for 86,567 neonates, and 194 were confirmed to have CH (100 males; F/M = 0.94; overall incidence 1:446). After the third birthday, reevaluation was performed in all (except 18 that were not accessible). From 176 patients, 81 (46%) were diagnosed with permanent CH, and 95 were discharged as transient. Considering the same percentage in the lost cases, the prevalence of permanent CH was found to be 1:970. TS performed for 53 of the permanent subjects found agenesis/dysgenesis in 25 (F:M = 15:10) and a normal result in 28 (F:M = 11:17), indicating dyshormonogenesis as the cause in more than 50% of subjects. Conclusions: The incidence of CH in this area was found to be higher than that in other countries but less than the incidence rate reported in central Iran. The large number of transient cases of CH suggests environmental or maternal causes for the incidence rather than a genetic basis.

Vitamin D status in diabetic children and adolescents.

INTRODUCTION: Besides its role in calcium homeostasis, vitamin D (VD) has an important immuno-mudulation effect. However, its role in autoimmune diseases such as type 1 diabetes is under discussion. This study designed to investigate serum VD status in children and adolescents with and without diabetes. MATERIALS AND METHODS: In a case-control study, 85 diabetic and 85 non-diabetic control (total 170) aged 1-15 yr. were enrolled. History of breast feeding and vitamin supplementation was obtained; growth indices and serum levels of Calcium, phosphorous, Alkaline-Phosphatase (ALP), Hemoglobin-A1c and VD were measured and analyzed. RESULTS: The mean values for VD in case and control groups were 12.80 ±â€¯10.59 and 15.85 ±â€¯9.92 nmol/L, respectively (p = 0.057). Serum VD status in these two groups was sufficient in 5.88% and 9.41%, insufficient in 18% and 14%, and deficient in 75.29% and 76.74%, respectively. Compared to the controls, diabetics had more history of breast-feeding (62.35% vs. 42.35%; p = 0.017) and higher serum ALP levels (772.34 ±â€¯309.89 vs. 657.99 ±â€¯395.11 U/L; p = 0.032). CONCLUSION: More frequency of breast-feeding, higher serum ALP and mildly lower serum level of VD in diabetics suggests a significant difference in VD status in diabetics compared to the healthy peers indicating a potential role of this deficiency in the disease process.