DOK7 congenital myasthenic syndrome: case series and review of literature.

BACKGROUND: Congenital myasthenic syndromes (CMS) are among the most challenging differential diagnoses in the neuromuscular domain, consisting of diverse genotypes and phenotypes. A mutation in the Docking Protein 7 (Dok-7) is a common cause of CMS. DOK7 CMS requires different treatment than other CMS types. Regarding DOK7's special considerations and challenges ahead of neurologists, we describe seven DOK7 patients and evaluate their response to treatment. METHODS: The authors visited these patients in the neuromuscular clinics of Tehran and Kerman Universities of Medical Sciences Hospitals. They diagnosed these patients based on clinical findings and neurophysiological studies, which Whole Exome Sequencing confirmed. For each patient, we tried unique medications and recorded the clinical response. RESULTS: The symptoms started from birth to as late as the age of 33, with the mean age of onset being 12.5. Common symptoms were: Limb-girdle weakness in 6, fluctuating symptoms in 5, ptosis in 4, bifacial weakness in 3, reduced extraocular movement in 3, bulbar symptoms in 2 and dyspnea in 2 3-Hz RNS was decremental in 5 out of 6 patients. Salbutamol was the most effective. c.1124_1127dupTGCC is the most common variant; three patients had this variant. CONCLUSION: We strongly recommend that neurologists consider CMS in patients with these symptoms and a similar familial history. We recommend prescribing salbutamol as the first-choice treatment option for DOK7 patients.

Homozygous Null TBX4 Mutations Lead to Posterior Amelia with Pelvic and Pulmonary Hypoplasia.

The development of hindlimbs in tetrapod species relies specifically on the transcription factor TBX4. In humans, heterozygous loss-of-function TBX4 mutations cause dominant small patella syndrome (SPS) due to haploinsufficiency. Here, we characterize a striking clinical entity in four fetuses with complete posterior amelia with pelvis and pulmonary hypoplasia (PAPPA). Through exome sequencing, we find that PAPPA syndrome is caused by homozygous TBX4 inactivating mutations during embryogenesis in humans. In two consanguineous couples, we uncover distinct germline TBX4 coding mutations, p.Tyr113∗ and p.Tyr127Asn, that segregated with SPS in heterozygous parents and with posterior amelia with pelvis and pulmonary hypoplasia syndrome (PAPPAS) in one available homozygous fetus. A complete absence of TBX4 transcripts in this proband with biallelic p.Tyr113∗ stop-gain mutations revealed nonsense-mediated decay of the endogenous mRNA. CRISPR/Cas9-mediated TBX4 deletion in Xenopus embryos confirmed its restricted role during leg development. We conclude that SPS and PAPPAS are allelic diseases of TBX4 deficiency and that TBX4 is an essential transcription factor for organogenesis of the lungs, pelvis, and hindlimbs in humans.

Comparing the effectiveness of Salvia officinalis, clotrimazole and their combination on vulvovaginal candidiasis: A randomized, controlled clinical trial.

AIM: To determine the effect of vaginal tablet of Salvia officinalis, alone and in combination with Clotrimazole, on the recovery of Vulvovaginal candidiasis. METHODS: In this triple-blind randomized controlled trial, 111 participants were randomly assigned into three groups of 37 patients using block randomization with block sizes of 6 and 9, and allocation ratio of 1:1:1: 100 mg vaginal tablet of Clotrimazole and Placebo (CP), 400 mg vaginal tablet of S. officinalis and Placebo (SP), and vaginal tablet of S. officinalis and Clotrimazole (SC), once daily for 7 days. On the seventh day after the treatment was ended up, Vulvovaginal candidiasis were examined by vaginal symptoms and wet test, and if positive, they were examined by culture in chrome agar Candida medium. RESULTS: Socio-demographic characteristics was similar (P > 0.05). Thirty-six, 36 and 35 patients, respectively in CP, SC and SP groups recruited in the study. The frequency of a positive wet test confirmed by Sabrodextrose agar medium 7 days after treatment was significantly lower in SC group than the reference group of CP (adjusted odds ratio = 0.09, 95% confidence interval: 0.93-0.932, P = 0.043). There was no significant difference between SP and CP group (P = 0.071, 95% confidence interval: 0.032-1.151, adjusted odds ratio = 0.192). Also, there was no significant difference between the three groups in terms of vaginal symptoms at the baseline (P > 0.05), however the statistical differences were indicated after the intervention in cheesy discharge, pruritus and Vulvovaginal edema (P < 0.05.(. CONCLUSION: S. officinalis in the form of vaginal tablet, alone and when combined with Clotrimazole, can treat the Vulvovaginal Candidiasis.

Clinical application of next generation sequencing for Mendelian disease diagnosis in the Iranian population.

Next-generation sequencing (NGS) has been proven to be one of the most powerful diagnostic tools for rare Mendelian disorders. Several studies on the clinical application of NGS in unselected cohorts of Middle Eastern patients have reported a high diagnostic yield of up to 48%, correlated with a high level of consanguinity in these populations. We evaluated the diagnostic utility of NGS-based testing across different clinical indications in 1436 patients from Iran, representing the first study of its kind in this highly consanguineous population. A total of 1075 exome sequencing and 361 targeted gene panel sequencing were performed over 8 years at a single clinical genetics laboratory, with the majority of cases tested as proband-only (91.6%). The overall diagnostic rate was 46.7%, ranging from 24% in patients with an abnormality of prenatal development to over 67% in patients with an abnormality of the skin. We identified 660 pathogenic or likely pathogenic variants, including 241 novel variants, associated with over 342 known genetic conditions. The highly consanguineous nature of this cohort led to the diagnosis of autosomal recessive disorders in the majority of patients (79.1%) and allowed us to determine the shared carrier status of couples for suspected recessive phenotypes in their deceased child(ren) when direct testing was not possible. We also highlight the observations of recessive inheritance of genes previously associated only with dominant disorders and provide an expanded genotype-phenotype spectrum for multiple less-characterized genes. We present the largest mutational spectrum of known Mendelian disease, including possible founder variants, throughout the Iranian population, which can serve as a unique resource for clinical genomic studies locally and beyond.

Possible cancer-causing capacity of COVID-19: Is SARS-CoV-2 an oncogenic agent?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown diverse life-threatening effects, most of which are considered short-term. In addition to its short-term effects, which has claimed many millions of lives since 2019, the long-term complications of this virus are still under investigation. Similar to many oncogenic viruses, it has been hypothesized that SARS-CoV-2 employs various strategies to cause cancer in different organs. These include leveraging the renin angiotensin system, altering tumor suppressing pathways by means of its nonstructural proteins, and triggering inflammatory cascades by enhancing cytokine production in the form of a "cytokine storm" paving the way for the emergence of cancer stem cells in target organs. Since infection with SARS-CoV-2 occurs in several organs either directly or indirectly, it is expected that cancer stem cells may develop in multiple organs. Thus, we have reviewed the impact of coronavirus disease 2019 (COVID-19) on the vulnerability and susceptibility of specific organs to cancer development. It is important to note that the cancer-related effects of SARS-CoV-2 proposed in this article are based on the ability of the virus and its proteins to cause cancer but that the long-term consequences of this infection will only be illustrated in the long run.

The Dopamine Gene Receptors (DRD1-5) Expression Alteration in Psoriasis Patients.

BACKGROUND: Psoriasis is a chronic inflammatory autoimmune disease that is considered linked to genetic and environmental factors such as stress. Since the neurotransmitter dopamine has a close association with stress configuration, it can be a candidate for relieving psoriasis representation. In addition to the CNS, immune cells can play a decisive role in regulating immune functions through dopamine synthesis and the expression of its receptors. Altered response of immune cells to dopamine as well as a distorted expression of dopamine receptors (DRs) in immune cells have been reported in some chronic inflammatory conditions. OBJECTIVE: This study aims the evaluation of dopamine receptor (DR1-DR5) gene expression in mononuclear blood cells of psoriatic patients in comparison with normal individuals. METHODS: We isolated peripheral mononuclear cells (PBMCs) from blood samples followed by total RNA extraction, cDNA synthesis, and real-time PCR using specific primer pairs. RESULTS: We found that all types of DRs are expressed in the PBMCs of normal and psoriatic individuals. We also concluded that compared to controls, DR2 and DR4 were overexpressed in psoriasis patients while DR3 was low-expressed. CONCLUSION: Increased expression of DR2 and DR4 along with decreased expression of DR3 in PBMCs of psoriasis patients not only provide new insight into the pathogenesis of psoriasis but may also be effective in designing future therapeutic strategies attributable to psoriasis.

Brief Report of Variants Detected in Hereditary Hearing Loss Cases in Iran over a 3-Year Period.

BACKGROUND: Diagnosis of hereditary hearing loss (HHL) as a heterogeneous disorder is very important especially in countries with high rates of consanguinity where the autosomal recessive pattern of inheritance is prevalent. Techniques such as next-generation sequencing, a comprehensive genetic test using targeted genomic enrichment and massively parallel sequencing (TGE + MPS), have made the diagnosis more cost-effective. The aim of this study was to determine HHL variants with comprehensive genetic testing in our country. METHODS: Fifty GJB2 negative individuals with HHL were referred to the Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, one of the reference diagnostic genetic laboratories in Iran, during a 3-year period between 2014 and 2017. They were screened with the OtoSCOPE test, the targeted genomic enrichment and massively parallel sequencing (TGE + MPS) platform after a detailed history had been taken along with clinical evaluation. RESULTS: Among 32 out of 50 GJB2 negative patients (64%), 34 known pathogenic and novel variants were detected of which 16 (47%) were novel, identified in 10 genes of which the most prevalent were CDH23, MYO7A and MYO15A. CONCLUSION: These results provide a foundation from which to make appropriate recommendations for the use of comprehensive genetic testing in the evaluation of Iranian patients with hereditary hearing loss.

De novo Mutation in CACNA1S Gene in a 20-Year-Old Man Diagnosed with Metabolic Myopathy.

The calcium channel, voltage-dependent, L-type, alpha 1S subunit (CACNA1S) gene encodes a skeletal Ca2+ channel which is involved in calcium-dependent processes such as muscle contraction and neurotransmitter release. Mutations in this gene have been accompanied by hypo- and normokalemic periodic paralysis, thyrotoxic periodic paralysis, and susceptibility to malignant hyperthermia. We report the clinical and genetic findings in a patient diagnosed with metabolic myopathy who had episodic attacks of muscle pain and weakness but with no family background of the disease. Next-generation sequencing (NGS) using a panel targeting metabolic myopathy and myotonia genes identified a de novo heterozygous pathogenic variant c.3724A>G, p.Arg1242Gly, in exon 30 of CACNA1S. As the second report of this variant, this case may broaden the CACNA1S-related disease spectrum to include normokalemic periodic paralysis.

Methylation pattern of ALX4 gene promoter as a potential biomarker for blood-based early detection of colorectal cancer.

BACKGROUND: To develop a non-invasive screening method for colorectal cancer, we evaluated the methylation of ALX4 gene promoter in serum samples from patients with colorectal cancer (CRC) and equal number of healthy individuals. MATERIALS AND METHODS: In serum samples from 25 patients with colorectal cancer and 25 healthy control subjects, isolated serum free-floating DNA was treated with sodium bisulfite and analyzed by methylation-specific polymerase chain reaction (MSP) with primers specific for methylated or unmethylated promoter CpG island sequences of the ALX4 gene. RESULTS: Methylation of the ALX4 gene promoter was present in the serum DNA of patients with adenoma and colorectal cancer. A sensitivity of 68% and specificity of 88% were achieved in the detection of promoter methylation in colorectal neoplasia samples. The difference in methylation status of the ALX4 promoter between the patients with colorectal neoplasia and the control group was statistically highly significant (P < 0.001). CONCLUSIONS: The results indicate that this serum free DNA test of methylation of the ALX4 gene promoter is a sensitive and specific method. Therefore in combination with other useful markers it seems ALX4 has the potential of a clinically useful test for the early detection of colorectal cancer.

Expression of prostaglandin I2 (prostacyclin) receptor in blood of migraine patients: A potential biomarker.

BACKGROUND: Migraine is the most common chronic neurological disorders that may be associated with vasodilatation. According to the role of prostaglandin I2 (prostacyclin) receptor (PTGIR) in migraine as a receptor, which acts in vasodilatation, we decided to study the changes of PTGIR expression in migraine patients in relation to a suitable control group. MATERIALS AND METHODS: Extracted mRNA from lymphocytes of 50 cases and 50 controls was used to synthesize cDNA. Real-time polymerase chain reaction was performed, and the data were analyzed. Our results show that PTGIR mRNA expression in cases was significantly higher than the control group (P = 0.010). RESULTS: In conclusion, mRNA expression of PTGIR in the blood of people with migraines could be considered as a biomarker. CONCLUSION: In addition, repression of PTGIR gene expression by methods such as using siRNA is probably suitable for therapy of migraine patients.

A miRNA-binding site single nucleotide polymorphism in the 3'-UTR region of the NOD2 gene is associated with colorectal cancer.

Colorectal cancer (CRC) is one of the common malignancies worldwide. Single nucleotide polymorphisms in miRNA-binding site on gene transcripts are reported to play important role in increased risk of CRC in different population. We performed a case-control study using 88 CRC patients and 88 non-cancer counterparts to evaluate the association between NOD2 rs3135500 polymorphism located at 3' untranslated region of the gene and risk of sporadic CRC. Genotyping of rs3135500 polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. We found a significant association of AA genotype with risk of CRC (adjusted OR 3.100, CI 1.621-5.930, p < 0.001). Also, significant difference in physical activity (p = 0.001) between case and control groups was found. We also found that individuals in control group were more aspirin or NSAID user compared to sporadic CRC cases (p = 0.002). In the case group, individuals with GG genotype consumed more aspirin or NSAID compared with AA+AG genotypes (33.3 vs. 9.6 %, adjusted OR 4.71, CI 1.25-17.76, p = 0.02). However, in the control group, individuals with AA+AG genotypes used more aspirin or NSAID compared with GG genotypes (47.2 vs. 11.4 %, adjusted OR 14 %, CI 0.05-0.47, p < 0.001).