Identification of Novel Mutations in the MMAA and MUT Genes among Methylmalonic Aciduria Families.

Background: Methylmalonic aciduria is a rare inherited metabolic disorder with autosomal recessive inheritance pattern. There are still MMA patients without known mutations in the responsible genes. This study aimed to identify mutations in Iranian MMA families using autozygosity mapping and NGS. Methods: Multiplex PCR was performed on DNAs isolated from 12 unrelated MMA patients and their family members using 19 STR markers flanking MUT, MMAA, and MMAB genes, followed by Sanger sequencing. WES was carried out in the patients with no mutation. Results: Haplotype analysis and Sanger sequencing revealed two novel, mutations, A252Vf*5 and G87R, within the MMAA and MUT genes, respectively. Three patients showed no mutations in either autozygosity mapping or NGS analysis. Conclusion: High-frequency mutations within exons 2 and 3 of MUT gene and exon 7 of MMAB gene are consistent with the global expected frequency of genetic variations among MMA patients.

Mutational Analysis and Genotype Investigation of Less Known Gaucher Mutations through Haplotype Analysis in Iranian Gaucher Patients.

Gaucher's disease (GD) is the most frequent lysosomal storage disorder resulting from a deficiency of the enzyme glucocerebrosidase (GBA) which causes the accumulation of glucocerebroside. More than 500 mutations have been reported on the GBA gene so far. In this study, we aimed to investigate more on the genotype of less known mutations through haplotype analysis to explain their disease-causing inheritance. Eight patients and three carriers from nine different families were enrolled in the study. DNA sequencing of all GBA gene's exons was performed and pathogenicity of the mutations was investigated. Using GBA gene-linked STR markers, allele segregations were determined in some families. A total of six different mutations were determined. Five and three patients were identified to carry mutations in homozygous and compound heterozygote patterns respectively, three participants also were identified as carriers. The most prevalent mutations were c.1448 T>C and RecNcil, however, three less common mutations were identified (i.e., c.1223 C>T, c.1315 A>G, and c.1214 G>C). In conclusion, we evaluated six different mutations in Iranian patients and elucidated the inheritance of the three less-known mutations by linkage analysis.

Immunological Evaluation of Pediatric Patients with Polyautoimmunity.

BACKGROUND: Autoimmunity can be the first or predominant manifestation in patients with primary immunodeficiency disorder, also referred to as inborn errors of immunity (IEI). This study aims to evaluate the immune status of pediatric patients with polyautoimmunity to identify those with underlying immune defects. METHODS: In this cross-sectional study, pediatric patients with polyautoimmunity including at least one confirmed autoimmune endocrine disease were enrolled. Demographic and clinical data were collected using a questionnaire based on medical records and direct family interviews. For each patient, a basic immunologic evaluation was performed. The clinical diagnosis was established according to the criteria of the European Society for Immunodeficiencies (ESID). Based on the presence or absence of a history of severe and/or recurrent infections, patients were divided into two groups for comparison. RESULTS: Thirty-nine patients, 18 males (46.2%) and 21 females (53.8%), were included. Fourteen patients (35.9%) had consanguineous parents. Fifteen patients (38.5%) had a history of severe and/or recurrent infections. The median (interquartile range: IQR) age of our patients at the time of evaluation was 11.1 (9-16) years. The median (IQR) age at the onset of infections and autoimmunities were 3 (1-10.8) and 5 (2.6-8) years, respectively. The most common infectious complications reported were pneumonia and candidiasis, each in 12.8% of the patients. The most prevalent autoimmune disorders were type 1 diabetes (74.3%) and autoimmune thyroiditis (58.9%). IEI was diagnosed in six patients (15.38%), five of which were from the group with severe or recurrent infections: three with selective IgA deficiency, two with common variable immunodeficiency (CVID), and one with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX), but without a history of infections. CONCLUSION: The occurrence of early onset polyautoimmunity in association with severe and/or recurrent infections or in patients with a positive family history should be a warning sign for physicians to initiate an evaluation for possible immunodeficiency disorders to prevent complications through early treatment.

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.

Next-generation sequencing identified novel truncating mutations in BBS9 causing Bardet Biedl syndrome in two Iranian consanguineous families.

OBJECTIVES: Bardet-Biedl syndrome (BBS) is an autosomal recessive pleiotropic ciliopathy, which includes multi-organ clinical manifestations. The known genes involved in the development of the disease account for the causality in about 80% of the examined cases. MATERIALS & METHODS: We investigated two Iranian unrelated clinically diagnosed BBS patients, using a targeted next-generation sequencing panel consisting of 18 known BBS genes. The detected variants were investigated in the pedigree and studied using in silico tools for their pathogenicity. Patients' phenotypes were also assessed. RESULTS: Novel homozygous variants were detected in BBS9 gene in each patient, c.2014C>T, p.Gln672Ter and c.673_674insAA, p.Gln225GlnfsX10. The variants were segregated in the corresponding pedigree and were authenticated to obtain enough evidence to be categorized as pathogenic variants. CONCLUSION: Patients with truncating mutations in the same gene seem to show similar phenotypic features. Detection of novel and family-specific mutations is typically expected in the genetic hereditary diseases in Iran, which can finally lead to prevent the recurrence of the disease in the consanguineous marriages.

The Prevalence of Selective and Partial Immunoglobulin A Deficiency in Patients with Autoimmune Polyendocrinopathy.

BACKGROUND: Autoimmune disorders are reported as presenting signs in patients with immunoglobulin A (IgA) deficiency. Herein, we aim to evaluate serum IgA among patients with autoimmune polyendocrinopathy. METHODS: Patients with two or more autoimmune endocrinopathies were selected and the serum IgA levels were measured. Patients with an isolated low serum IgA (<7 mg/dL) after exclusion of other causes of hypogammaglobulinemia were considered as selective IgA deficiency (SIgAD), while partial IgA deficiency (PIgAD) was defined as IgA levels below lower limits of IgA normal range for age but higher than 7 mg/dL. RESULTS: Fifty-three patients (19 [35.8%] male and 34 [64.2%] female) with autoimmune polyendocrinopathy enrolled in the study. Parental consanguinity and positive family history of autoimmunity were reported in 38.0% and 52.9% of patients, respectively. Overall, IgA deficiency was observed in 5 (9.4%) patients including PIgAD in 3 (5.7%) and SIgAD in 2 (3.8%) patients. Among IgA deficient patients, the first autoimmune disorder was developed at earlier ages (p = .002), and the prevalence of infection (p = .002), lymphoproliferation (p = .021), and overlap between insulin-dependent diabetes mellitus and autoimmune thyroiditis (p = .032) were significantly higher than patients with normal IgA. Also, the number of autoimmune comorbidities was closely correlated with the occurrence of IgA deficiency (p = .008). CONCLUSION: The prevalence of IgA deficiency in patients with autoimmune polyendocrinopathy is higher than that in the general population. In these patients, immunologic workup may lead to early diagnosis of inborn error of immunity, which can positively impact the evolution of complications and even management of the autoimmune disorders.

Study protocol of a randomized controlled clinical trial investigating the effects of omega-3 supplementation on endothelial function, vascular structure, and metabolic parameters in adolescents with type 1 diabetes.

BACKGROUND: Type 1 diabetes is a main health burden with several related comorbidities. It has been shown that endothelial function, vascular structure, and metabolic parameters are considerably disrupted in patients with type 1 diabetes. Omega-3 as an adjuvant therapy may exert profitable effects on type 1 diabetes and its complications by improving inflammation, oxidative stress, immune responses, and metabolic status. Because no randomized clinical trial has examined the effects of omega-3 consumption in children and adolescents with type 1 diabetes; the present study aims to close this gap. METHODS: This investigation is a randomized clinical trial, in which sixty adolescents with type 1 diabetes will be randomly assigned to receive either omega-3 (600 mg/day) or placebo capsules for 12 weeks. Evaluation of anthropometric parameters, flow-mediated dilation (FMD) as an endothelial function marker, carotid intima-media thickness (CIMT) as a vascular structure marker, proteinuria, biochemical factors including glycemic and lipid profile, blood urea nitrogen (BUN), creatinine, high-sensitivity C-reactive protein (hs-CRP), and erythrocyte sedimentation rate (ESR), as well as blood pressure will be done at the baseline and end of the trial. Also, dietary intake and physical activity will be assessed throughout the study. Statistical analysis will be performed using the SPSS software (Version 24), and P < 0.05 will be considered statistically meaningful. DISCUSSION: It is hypothesized that omega-3 supplementation may be beneficial for the management of type 1 diabetes and its complications by reducing inflammation and oxidative stress and also modulating immune responses and glucose and lipid metabolism through various mechanisms. The present study aims to investigate any effect of omega-3 on patients with type 1 diabetes. ETHICAL ASPECTS: This trial received approval from Medical Ethics Committee of Iran University of Medical Sciences, Tehran, Iran (IR.IUMS.REC.1400.070). TRIAL REGISTRATION: Iranian Registry of Clinical Trials IRCT20210419051010N1 . Registered on 29 April 2021.

Clinical and Paraclinical Characteristics of Non-Classic Phenylketonuria.

OBJECTIVE: Phenylketonuria (PKU) is one of the most common inherited metabolic diseases, which is classified into classic and non-classic types. It is estimated that 2% of children with PKU develop a severe and progressive neurological disease, called non-classic (malignant) PKU. This study aimed to demonstrate the clinical features, laboratory findings, and diagnostic/therapeutic characteristics of non-classic PKU patients referred to a tertiary referral center for children in Tehran, Iran. MATERIALS & METHODS: In this study, background information, such as gender and age, clinical manifestations, laboratory findings, and response rate to conventional treatment, was investigated in patients with non-classic PKU, who were referred to Mofid Children's Hospital in Tehran, Iran, through neonatal screening. RESULTS: Twenty patients with a diagnosis of non-classic PKU were included in this study. The mean age of the patients was 6.00±2.81 years (range: 2-12 years), and 45.0% were male. In patients with a late diagnosis, the most common presentations were motor developmental delay (15.0%), skin and cutaneous manifestations (15.0%), seizure (5.0%), and restlessness (5.0%). The overall response rate to treatment was 85.0%. Factors that predict good response to treatment included female gender, higher neopterin level, and lower age at diagnosis and management. CONCLUSION: In conclusion, about half of patients with non-classic PKU remain asymptomatic, which is due to early diagnosis via neonatal screening. Also, higher age at diagnosis and treatment, besides low neopterin levels, may be useful as prognostic factors.

Analysis of glucocerebrosidase (GBA) gene mutations in Iranian patients with Gaucher disease.

OBJECTIVES: Gaucher disease (GD) is the most common autosomal recessive disorder of glycolipid storage. It results from mutations in the glucocerebrosidase (GBA) gene and leads to GBA deficiency. Different mutations are associated with different phenotypes in the three major types of GD. MATERIALS AND METHODS: The spectrum of mutations in GBA gene in 26 unrelated patients with GD from different Iranian populations was determined by DNA sequencing, polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP), and amplification-refractory mutation system (ARMS) methods. An in silico analysis was also performed for novel mutations. RESULTS: Six new mutations were identified in this study. The newly detected mutations that could be theoretically harmful included p.I200T (c.599T>C), p.H312D (c.934C>G), p.L325S (c.974T>C), p.L393V (c.1177C>G), p.S439G (c.1315A>G), and p.M455R (c.1365G>A). Also, p.L483P, p.N409S, p.W420X, p.E379K, p.R398Q, p.N227S, p.R202Q, and p.D448H mutations were identified in the patients. Besides, two new complex mutations, namely, p.S439G/p.S439G+p.E379K/- and p.R202Q/p.R202Q+p.N227S/p.N227S, were detected. The most common GBA mutation in the population was p.L483P with an allele frequency of 32.7%, followed by p.N409S (19.2%). CONCLUSION: The present study detected six new mutations of GBA gene among GD patients. Two mutations (p.L483P and p.N409S) were especially common among Iranians; this finding can be used in implementing screening programs and understanding the molecular basis of GD.

Once in a Blue Moon, a Very Rare Coexistence of Glutaric Acidemia Type I and Mucopolysaccharidosis Type IIIB in a Patient

Background: Glutaric acidemia (GAI) and mucopolysaccharidosis type IIIB (MPSIIIB) are two rare genetic disorders caused by pathogenic variants in two different genes. Here, we report a coexistence of these two different rare disorders in an individual. Methods: A four-year-old Iranian boy born to first-cousin parents suspected to have MPSIIIB and/or GAI was investigated in this study. Targeted genomic enrichment and next-generation sequencing were used to examine genes related to MPS and GA. Sanger sequencing was performed to confirm the results. Results: Two homozygous likely pathogenic variants in α-N-acetylglucosaminidase (NAGLU) and GCDH genes were found and confirmed in the proband. Conclusion: A combination of specific features of two different diseases in a patient has been reported here. More studies on this case and similar cases can provide more information about the effect of simultaneous pathogenic variants in different genes.

Oxidative Stress Parameters, Trace Elements, and Lipid Profile in Iranian Patients with Gaucher Disease.

Gaucher disease (GD) is most frequent disorder of glycolipid storage. The glucosylceramide accumulation might lead to oxidative stress and changes in lipid profile. Regarding the main role of trace elements in hematopoiesis and oxidative stress, this study was aimed to evaluate the zinc and copper levels, three oxidative stress parameters, and lipid profile in GD. Thirty-three patients with GD along with 64 age- and sex-matched healthy controls participated in the study. The levels of zinc and copper were determined using atomic absorption/flame emission spectrophotometer. Malondialdehyde level was measured using HPLC. Total antioxidant capacity (TAC), catalase activity, and lipid profile were assessed using colorimetric methods. Data were analyzed using SPSS software version 16.0. Significant decrease in the serum levels of Zn (p < 0.001) and Cu (p < 0.001) was observed in patients with GD compared to controls. Subjects in control group showed significantly higher levels of TAC than patients with GD (p < 0.001). In contrast, plasma concentration of malondialdehyde was insignificantly higher in patients with GD than controls (p = 0.06). There was a direct correlation between TAC and hemoglobin concentration (p = 0.035; r = 0.369) in patients with GD. Furthermore, the calculated area under receiver operating characteristic curve for HDL cholesterol was equal to 0.938. The results showed that both zinc and copper levels decreased in patients with GD. Patients with GD showed decreased serum content of TAC. It was found that improving the deficiency of zinc and copper by supplementing them could be useful in management of patients with GD.

Mutation analysis and clinical characterization of Iranian patients with mucopolysaccharidosis type I.

BACKGROUND: Mucopolysaccharidosis type I (MPSI) is a rare autosomal recessive disorder caused by a deficiency of α-l-iduronidase (IDUA) encoded by the IDUA gene. We examined the mutation spectrum of the IDUA gene to explain the clinical, biochemical, and molecular features in 21 Iranian patients with MPSI. METHODS: Sanger sequencing was used to measure the IDUA gene sequence in the coding region and exon-intron boundaries. We recorded the clinical findings of studied patients at the first diagnosis of disease and then during the treatment and follow-up. RESULTS: Five different missense disease-causing mutations were determined in our patient groups, indicating 90.48% of detection rate. The most widespread mutation was the p.Y109H, occurring in 15.625% of all alleles, which was reported for the first time in our study. Other frequent mutations were as follows: p.Ser157Pro (12.5%), p.Gly84Arg (12.5%), p.Asp257His (9.375%), and p.Asp301Glu (9.375%). Three ones of them were new missense mutations: p.Ser157Pro, p.Asp257His, and p.Asp301Glu. DISCUSSION: The results of this study explain the different spectrum of IDUA gene mutations in our patients with MPSI. We introduced here 32 different variants including four new variants: p.Y109H (15.625%), p.S157P (12.5%), p.D257H (9.375%), and p.D301E (9.375%). In this series, there was no relationship between the happening of clinical features and genotype variations and biochemical findings.

Gaucher Disease: New Expanded Classification Emphasizing Neurological Features.

Gaucher disease (GD) is a rare inherited metabolic disorder and the most common lysosomal storage disorder, caused by a deficiency in glucocerebrosidase enzyme activity. It has been classified according to the neurological manifestations into three types: type 1, without neuropathic findings, type 2 with acute infantile neuropathic signs and type 3 or chronic neuropathic form. However, report of new variants has led to the expansion of phenotype as a clinical phenotype of GD considered as a continuum of phenotypes. Therefore, it seems that a new classification is needed to cover new forms of the disease.

Molecular genetics of a cohort of 635 cases of phenylketonuria in a consanguineous population.

Phenylketonuria (PKU) is an inborn error of amino acid metabolism caused by mutations in the phenylalanine hydroxylase (PAH) gene, characterized by intellectual deficit and neuropsychiatric complications in untreated patients with estimated frequency of about one in 10,000 to 15,000 live births. PAH deficiency can be detected by neonatal screening in nearly all cases with hyperphenylalaninemia on a heel prick blood spot. Molecular testing of the PAH gene can then be performed in affected family members. Herein, we report molecular study of 635 patients genetically diagnosed with PKU from all ethnicities in Iran. The disease-causing mutations were found in 611 (96.22%) of cases. To the best of our knowledge, this is the most comprehensive molecular genetics study of PKU in Iran, identifying 100 distinct mutations in the PAH gene, including 15 previously unreported mutations. Interestingly, we found unique cases of PKU with uniparental disomy, germline mosaicism, and coinheritance with another Mendelian single-gene disorder that provides new insights for improving the genetic counseling, prenatal diagnosis (PND), and/or pre-implantation genetic diagnosis (PGD) for the inborn error of metabolism group of disorders.

Relationship Between Obesity and Liver Enzymes Levels in Turner's Syndrome.

BACKGROUND: Liver enzyme abnormalities have been reported in Turner's syndrome (TS). There are some studies about possible causes of abnormal levels of liver enzymes. One of the main suggestions is obesity. The study aimed to determine the relationship between obesity and liver enzymes levels in patients with TS. METHODS: Forty-one karyotype-proven TS patients referred to Endocrinology and Metabolism Research Center were included in this cross-sectional study. Height and weight of patients were measured and their body mass index (BMI) was calculated. The patients were divided into two groups as the control group including 27 cases (65.8%) with normal BMI (defined as < 85th percentile for age and gender), and the overweight group including 14 cases (34.2%) (defined as BMI > 85th percentile for age and gender). Serum levels of aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (AlkPh) were measured. RESULTS: There were no statistically significant differences regarding AST (27 ± 2.7 vs. 29.6 ± 5.85 U/L; P = 0.3), ALT (20.1 ± 2.45 vs. 22.2 ± 5.85 U/L; P = 0.5), and AlkPh (583.4 ± 2.45 vs. 472.8 ± 161.5 U/L; P = 0.28) between overweight TS patients and those with normal BMI. CONCLUSION: There was no significant difference in liver enzyme levels between TS patients with normal BMI and those who were overweight.

In silico analysis of novel mutations in maple syrup urine disease patients from Iran.

Maple Syrup Urine Disease (MSUD) is a rare autosomal recessive disorder of branched-chain amino acid (BCAA) metabolism. The disease is mainly caused by mutations either in the BCKDHA, BCKDHB, DBT or DLD genes encoding components of the E1α, E1ß, E2 and E3 subunits of branched-chain α-keto acid dehydrogenase complex (BCKDC), respectively. BCKDC is a mitochondrial enzyme which is responsible for the normal breakdown of BCAA. The rate of consanguineous marriage in Iran is 38.6 %, so the prevalence of autosomal recessive disorders is higher in comparison to other countries. Consanguinity increases the chance of the presence of pathogenic mutations in a homoallelic state. This phenomenon has made homozygosity mapping a powerful tool for finding the probable causative gene in heterogeneous disorders like IEM (Inborn Errors of Metabolism). In this study, two sets of multiplex polymorphic STR (Short Tandem Repeat) markers linked to the above-mentioned genes were selected to identify the probable pathogenic gene in the studied families. The families who showed a homozygous haplotype for the STR markers of the BCKDHB gene were subsequently sequenced. Four novel mutations including c.633 + 1G > A, c.988G > A, c.833_834insCAC, and a homozygous deletion of whole exon 3 c. (274 + 1_275-1) _(343 + 1_344-1), as well as one recently reported (c. 508G > T) mutation have been identified. Interestingly, three families shared a common haplotype structure along with the c. 508G > T mutation. Also, four other families revealed another similar haplotype with c.988G > A mutation. Founder effect can be a suggestive mechanism for the disease. Additionally, structural models of MSUD mutations have been performed to predict the pathogenesis of the newly identified variants.

Chitotriosidase Activity and Gene Polymorphism in Iranian Patients with Gaucher Disease and Sibling Carriers.

OBJECTIVE: Chitotriosidase (CT) activity is a useful biomarker for diagnosis and monitoring of Gaucher disease (GD). Its application is limited by some variants in the CT gene. Two main polymorphisms are 24 bp duplication and G102S led to reduce CT activity. The aim of this study was to determine these variants influencing on plasma CT activity. MATERIALS & METHODS: Blood samples were collected from 33 patients with GD, 15 sibling carriers and 105 healthy individuals serving as controls. CT activity was measured using 4-methylumbelliferyl-ß-D-N,N',N″triacetylchitotrioside substrate in plasma samples. The CT genotypes of 24 bp duplication and G102S variants were determined using PCR and PCR-RFLP. RESULTS: Untreated GD patients had a significantly higher CT activity compared to treated patients (P = 0.021). In addition, chitotriosidase activity in carriers was higher rather than controls. Allele frequencies of 24 bp duplication in GD patients, sibling carriers and controls were 0.21, 0.266 and 0.29 and for G102S were 0.318, 0.366 and 0.219, respectively. Different G102S genotypes had not significant effect on CT activity. Chitotriosidase activity has a positive correlation with age in normal group, carriers, and negative correlation with hemoglobin in GD patients. Using cut-off level of 80.75 nmol/ml/h, sensitivity and specificity of CT activity were 93.9% and 100%, respectively. CONCLUSION: Chitotriosidase activity is a suitable biomarker for diagnosis and monitoring of GD. Determination of 24 bp duplication is helpful for more accurate monitoring the GD patient's therapy. However, it seems that, specifying of the G102S polymorphism is not required for Iranian GD patients.

Whole Exome Sequencing Reveals a BSCL2 Mutation Causing Progressive Encephalopathy with Lipodystrophy (PELD) in an Iranian Pediatric Patient.

BACKGROUND: Progressive encephalopathy with or without lipodystrophy is a rare autosomal recessive childhood-onset seipin-associated neurodegenerative syndrome, leading to developmental regression of motor and cognitive skills. In this study, we introduce a patient with developmental regression and autism. The causative mutation was found by exome sequencing. METHODS: The proband showed a generalized hypertonia and regression of all developmental milestones. Based on the advantages of next-generation sequencing (NGS), whole exome sequencing (WES) was requested. The functional significance of variants was evaluated by NGS-specific prediction servers. Sanger sequencing was used for segregation analysis in the family. RESULTS: There was no specific sign in the clinical and paraclinical investigations of the patient to establish a conclusive clinical diagnosis. WES detected a known homozygous nonsense mutation in BSCL2 (NM_001122955.3:c. 985C>T; p.Arg329*). The variant is segregating in the pedigree with an autosomal recessive pattern. CONCLUSION: Exome sequencing is a robust method for identifying the candidate gene variants in Mendelian traits.

Identification of six novel mutations in Iranian patients with maple syrup urine disease and their in silico analysis.

Maple syrup urine disease (MSUD) is a rare inborn error of branched-chain amino acid metabolism. The disease prevalence is higher in populations with elevated rate of consanguineous marriages such as Iran. Different types of disease causing mutations have been previously reported in BCKDHA, BCKDHB, DBT and DLD genes known to be responsible for MSUD phenotype. In this study, two sets of multiplex polymorphic STR (Short Tandem Repeat) markers linked to the above genes were used to aid in homozygosity mapping in order to find probable pathogenic change(s) in the studied families. The families who showed homozygote haplotype for the BCKDHA gene were subsequently sequenced. Our findings showed that exons 2, 4 and 6 contain most of the mutations which are novel. The changes include two single nucleotide deletion (i.e. c. 143delT and c.702delT), one gross deletion covering the whole exon four c.(375+1_376-1)_(8849+1_885-1), two splice site changes (c.1167+1G>T, c. 288+1G>A), and one point mutation (c.731G>A). Computational approaches were used to analyze these two novel mutations in terms of their impact on protein structure. Computational structural modeling indicated that these mutations might affect structural stability and multimeric assembly of branched-chain α-keto acid dehydrogenase complex (BCKDC).

A Rare Case of Ovarian Hyperstimulation Syndrome in a Preterm Infant.

Ovarian hyperstimulation syndrome is a rare disease among preterm infants. This syndrome was first described in 1985 in four infants with a gestational age of <30 weeks. Several explanations for this syndrome have been suggested namely the immaturity of Hypothalamic-Pituitary-Gonadal (HPG) axis, lack of negative feedback, increased sensitivity of Follicle Stimulating Hormone (FSH) receptors due to mutation and high level of estradiol. In this report, a case of hyperstimulation syndrome in a newborn with gestational age of 30 weeks is presented and the probable mechanisms in the literature are discussed.