A novel missense variant in EIF2B5 identified in a consanguineous Iranian family with vanishing white matter disease and a brief review of the literature.

Vanishing of white matter (VWM) is a hereditary heterogeneous brain disorder that most often affects children. However, the onset of the disease varies from childhood to adulthood. VWM is caused by mutations in one of the five genes encoding subunits of the eukaryotic initiation factor eIF2B. In the current study, we aimed to determine the genetic cause of VWM in a large consanguineous Iranian family with three affected members. Next-generation sequencing was conducted on the proband to determine the underlying cause of VWM. The identified variant was validated by PCR-Sanger sequencing in the patient and was also segregated in his parents and two other affected members of the pedigree. The potential functional effects of this mutation within EIF2B5 were predicted by in silico analysis. We have also reviewed all EIF2B5 disease-causing variants and available clinical features of each patient reported in HGMD Professional 2022.2. A novel homozygous variant c.746T>G [p.Ile249Ser] was detected in EIF2B5 which was co-segregated with the disease in all affected family members in an autosomal recessive manner. All employed in silico prediction tools and 3D structure analysis for the novel mutation also supported the pathogenicity of this variant. Our study not only expanded the spectrum of the pathogenic variants in EIF2B5 but also presented a literature review on EIF2B5-related conditions that provide a comprehensive picture of the genetic nature of this gene and phenotypic variability in patients.

A Novel Mutation in the OXCT1 Gene Causing Succinyl-CoA:3-Ketoacid CoA Transferase (SCOT) Deficiency Starting with Neurologic Manifestations.

Succinyl-CoA:3-oxoacid CoA-transferase (SCOT) deficiency is an inborn error of ketone body utilization characterized by intermittent ketoacidosis crises. This study reports the first Iranian patient with SCOT deficiency who presented with seizure and hypotonia at birth. Accordingly, she was consequently re-hospitalized due to hypotonia and respiratory distress. Laboratory tests revealed hyperammonemia, ketonuria, and metabolic acidosis. Besides, the plasma glucose level was normal without any other abnormality. Despite treatment with high-dose bicarbonate, severe acidosis persisted. Poor response to treatment raised a significant diagnostic challenge among specialists until genetic investigation identified a homozygous nonsense mutation (c.79G>T; p.Gly27*) in the OXCT1 gene (NM_000436), causing SCOT deficiency. Genetic studies help clinicians achieve a definite diagnosis of such metabolic disorders. In this case, the accurate and early diagnosis of SCOT deficiency opened new therapeutic possibilities, including frequent carbohydrate-rich meals and low fat and protein diet. Moreover, our findings expand the mutational and clinical spectrum of SCOT deficiency.

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.

Evaluation of modulatory effects of saffron (Crocus sativus L.) aqueous extract on oxidative stress in ischemic stroke patients: a randomized clinical trial.

OBJECTIVES: Saffron (Crocus sativus L.) has been widely used in traditional medicine as a treatment of nervous disorders. Saffron as an antioxidant can be considered effective for treatment of oxidative stress in ischemia stroke. Therefore, the aim of the present study was to investigate the role of aqueous extract of saffron in reducing oxidative stress in ischemic strokes patients. METHODS: Forty patients with acute ischemic stroke were randomly divided into two groups including control group and saffron group. During 4 days of experiment, control group received routine stroke care and saffron group received routine care plus capsule of saffron 400 mg/day (200 mg twice per day). Then, two groups were compared using the National Institute of Health Stoke Scale (NIHSS) and serum oxidative stress biomarkers, at the time of hospital admission and 4 days later as well. RESULTS: On the fourth day after ischemic stroke onset, antioxidant enzymes activities and glutathione (GSH) and total antioxidant capacity (TAC) levels were higher in the saffron group compared to the control group, while malondialdehyde (MDA) level was lower. In addition, the severity of stroke, based on the NIHSS scores, was significantly reduced after 4 days in the saffron group. The severity of stroke was negatively correlated with the levels of GSH and TAC and positively correlated with MDA level. CONCLUSIONS: Saffron has modulatory effects on ischemic-induced oxidative stress due to its free radical scavenging and antioxidant properties. Thus, saffron extract can be considered as a potential candidate therapy of the ischemic brain.

Whole-Exome Sequencing Identified a Novel Variant (C.405_422+39del) in DSP Gene in an Iranian Pedigree with Familial Dilated Cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) is a progressive heart condition characterized by left ventricular chamber enlargement associated with systolic heart failure and prolonged action potential duration. Genetic variations in genes that encode cytoskeleton, sarcomere, and nuclear envelope proteins are responsible for 45% of cases. In our study, we focused on a pedigree with familial DCM to decipher the potential genetic cause(s) in affected members developing arrhythmia, end-stage heart failure, and sudden death. METHODS: Whole-exome sequencing (WES) was exploited for a 27-year-old heart-transplanted female as the proband, and the derived data were filtered using the standard pipelines. RESULTS: A 57-nucleotide deletion (c.405_422+39del) in the desmoplakin gene (DSP) (NM_004415.4) was identified as a novel pathogenic variant. Familial segregation analysis indicated that this variant is present in clinically affected members and absent in unaffected members. CONCLUSION: It seems that the detected variant induces intron retention, resulting in a premature stop codon in intron 3 of DSP leading to production of a truncated, nonfunctional protein. Additionally, it can trigger a nonsense-mediated mRNA decay pathway associated with inhibition of protein production. The present study results illustrated that a novel deletion in DSP can cause DCM in an Iranian family.

Dysfunction of the ciliary ARMC9/TOGARAM1 protein module causes Joubert syndrome.

Joubert syndrome (JBTS) is a recessive neurodevelopmental ciliopathy characterized by a pathognomonic hindbrain malformation. All known JBTS genes encode proteins involved in the structure or function of primary cilia, ubiquitous antenna-like organelles essential for cellular signal transduction. Here, we used the recently identified JBTS-associated protein armadillo repeat motif-containing 9 (ARMC9) in tandem-affinity purification and yeast 2-hybrid screens to identify a ciliary module whose dysfunction underlies JBTS. In addition to the known JBTS-associated proteins CEP104 and CSPP1, we identified coiled-coil domain containing 66 (CCDC66) and TOG array regulator of axonemal microtubules 1 (TOGARAM1) as ARMC9 interaction partners. We found that TOGARAM1 variants cause JBTS and disrupt TOGARAM1 interaction with ARMC9. Using a combination of protein interaction analyses, characterization of patient-derived fibroblasts, and analysis of CRISPR/Cas9-engineered zebrafish and hTERT-RPE1 cells, we demonstrated that dysfunction of ARMC9 or TOGARAM1 resulted in short cilia with decreased axonemal acetylation and polyglutamylation, but relatively intact transition zone function. Aberrant serum-induced ciliary resorption and cold-induced depolymerization in ARMC9 and TOGARAM1 patient cell lines suggest a role for this new JBTS-associated protein module in ciliary stability.

Adaptive synchronization of chaotic systems with hysteresis quantizer input.

This paper proposes two new designing methods of adaptive controllers in order to synchronize uncertain nonlinear chaotic systems with input quantization. The hysteresis quantizer, which is a class of sector-bounded quantizers, has been used to quantize the control signal. This can avoid the possible chattering caused by some conventional controllers. Two adaptive robust schemes are proposed to accomplish chaos synchronization of master and slave systems in presence of unknown parameters and uncertainties. The proposed controllers in this paper do not require the restrictive conditions for quantized parameters in contrast to some available control techniques for systems with input quantization. In addition, asymptotic stability of the proposed adaptive controllers is also verified analytically. Finally, the proposed controller is applied to a chaotic gyroscope and also to a Micro-Electro-Mechanical-System to validate its efficiency and robustness.

Protective properties of the aqueous extract of saffron (Crocus sativus L.) in ischemic stroke, randomized clinical trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Crocus sativus L. has been used throughout the world in traditional medicine as a treatment for neurological disorders such as depression. Growing attention is currently being paid to the use of neuroprotective agents in ischemic strokes. AIM OF THE STUDY: This study assed the effect of saffron as a neuroprotective natural product in cerebral ischemia in human. STUDY DESIGN: Patients with acute ischemic stroke were randomly allocated to receive either routine stroke care (control group, n = 20) or routine care plus aqueous extract of saffron capsule (200 mg/day) (saffron-treated group, n = 19). Both groups were monitored during their four-day hospital stay and the three-month follow-up period. The groups were compared in terms of short- and long-term effects of saffron capsules using the National Institute of Health Stoke Scale (NIHSS), Barthel Scale, and serum neuron specific enolase (NSE), Brain-derived neurotrophic factor (BDNF), S100 levels. RESULTS: Based on the NIHSS, the severity of stroke during the first four days was significantly lower in the saffron-treated group than in the control group (P < 0.05). Compared to the levels on the first day, serum NSE and s100 levels were significantly decreased and BDNF concentration was increased in the saffron-treated group on the fourth day. Also, our results showed there was a negative significant non-linear cubic regression between BDNF concentration and score of NIHSS. At the end of the three-month follow-up period, the mean Barthel index was significantly higher in the saffron-treated group than in the control group (P < 0.001). CONCLUSION: The results of this study confirmed the short and long-term neuroprotective effects of aqueous extract of saffron on ischemic stroke in humans.

Measuring Serum Level of Ionized Magnesium in Patients with Migraine.

OBJECTIVE: Migraine is known as one of the most disabling types of headache. Among the variety of theories to explain mechanism of migraine, role of serum magnesium is of great importance. Serum magnesium, as a pathogenesis factor, was considerably lower in patients with migraine. We established this study to see if serum ionized magnesium, not its total serum level, was different in migraineurs from normal individuals. MATERIALS & METHODS: In this case control study, all participants were recruited from Neurology Clinic of Imam Hossein Hospital, Tehran, Iran. Ninety-six people were entered in the study, 48 for each of case and control groups. The two groups were matched by age and sex. Migrainous patients were selected according to the criteria of International Headache Society. Various characteristics of headache were recorded based on patients' report. Controls had no history of migraine or any significant chronic headaches. Serum ionized magnesium level was measured in both of the case and control groups and the results were compared to each other. P value of <0.05 was considered as significant. RESULTS: Case group consisted of 13 males, 35 females, and control group included 14 males, as well as 34 females. Mean age was 33.47± 10.32 yr for case and 30.45 ±7.12 yr for control group. Twenty-eight patients described the intensity of their headaches as moderate; 15 patients had severe and the 5 remainders had only mild headaches. Mean serum level of ionized Mg was 1.16± 0.08 in case group and 1.13± 0.11 in control group of no significant difference (P >0.05). CONCLUSION: Serum ionized magnesium, which is the active form of this ion, was not significantly different in migraineurs and those without migraine. This may propose a revision regarding pathogenesis of migraine and question the role of magnesium in this type of headache.

Secondary headaches attributed to arterial hypertension.

Mild (140 to 159/90 to 99 mmHg) or moderate (160 to 179/100 to 109 mmHg) chronic arterial hypertension does not appear to cause headache. Whether moderate hypertension predisposes patients to headache at all remains controversial, but there is little evidence that it does. Ambulatory blood pressure monitoring in patients with mild and moderate hypertension has shown no convincing relationship between blood pressure fluctuations over a 24-hour period and presence or absence of headache. However, headaches are associated to various disorders that lead to abrupt, severe, and paroxysmal elevations in blood pressure. In this paper, the secondary headaches attributed to acute crises of hypertension and the criteria for diagnosing each of them have been reviewed. These are headaches attributed to pheochromocytoma, hypertensive crisis without encephalopathy, hypertensive encephalopathy, pre-eclampsia, eclampsia, and acute pressure response to exogenous agents.