Cohort profile update: Tehran cardiometabolic genetic study.

The Tehran cardiometabolic genetic study (TCGS) is a large population-based cohort study that conducts periodic follow-ups. TCGS has created a comprehensive database comprising 20,367 participants born between 1911 and 2015 selected from four main ongoing studies in a family-based longitudinal framework. The study's primary goal is to identify the potential targets for prevention and intervention for non-communicable diseases that may develop in mid-life and late life. TCGS cohort focuses on cardiovascular, endocrine, metabolic abnormalities, cancers, and some inherited diseases. Since 2017, the TCGS cohort has augmented by encoding all health-related complications, including hospitalization outcomes and self-reports according to ICD11 coding, and verifying consanguineous marriage using genetic markers. This research provides an update on the rationale and design of the study, summarizes its findings, and outlines the objectives for precision medicine.

Clinical presentation and natural history of infantile-onset ascending spastic paralysis from three families with an ALS2 founder variant.

Biallelic mutations of the alsin Rho guanine nucleotide exchange factor (ALS2) gene cause a group of overlapping autosomal recessive neurodegenerative disorders including infantile-onset ascending hereditary spastic paralysis (IAHSP), juvenile primary lateral sclerosis (JPLS), and juvenile amyotrophic lateral sclerosis (JALS/ALS2), caused by retrograde degeneration of the upper motor neurons of the pyramidal tracts. Here, we describe 11 individuals with IAHSP, aged 2-48 years, with IAHSP from three unrelated consanguineous Iranian families carrying the homozygous c.1640+1G>A founder mutation in ALS2. Three affected siblings from one family exhibit generalized dystonia which has not been previously described in families with IAHSP and has only been reported in three unrelated consanguineous families with JALS/ALS2. We report the oldest individuals with IAHSP to date and provide evidence that these patients survive well into their late 40s with preserved cognition and normal eye movements. Our study delineates the phenotypic spectrum of IAHSP and ALS2-related disorders and provides valuable insights into the natural disease course.

Examining the clinical and genetic spectrum of maturity-onset diabetes of the young (MODY) in Iran.

Maturity-onset diabetes of the young (MODY) is an uncommon monogenic type of diabetes mellitus. Detecting genetic variants for MODY is a necessity for precise diagnosis and treatment. The majority of MODY genetic predisposition has been documented in European populations and a lack of information is present in Iranians which leads to misdiagnosis as a consequence of defects in unknown variants. In this study, using genetic variant information of 20,002 participants from the family-based TCGS (Tehran Cardiometabolic Genetic Study) cohort, we evaluated the genetic spectrum of MODY in Iran. We concentrated on previously discovered MODY-causing genes. Genetic variants were evaluated for their pathogenicity. We discovered 6 variants that were previously reported in the ClinVar as pathogenic/likely pathogenic (P/LP) for MODY in 45 participants from 24 families (INS in 21 cases, GCK in 13, HNF1B in 8, HNF4A, HNF1A, and CEL in 1 case). One potential MODY variant with Uncertain Risk Allele in ClinVar classification was also identified, which showed complete disease penetrance (100%) in four subjects from one family. This is the first family-based study to define the genetic spectrum and estimate the prevalence of MODY in Iran. The discovered variants need to be investigated by additional studies.

Clinical and neuroradiological spectrum of biallelic variants in NOTCH3.

BACKGROUND: NOTCH3 encodes a transmembrane receptor critical for vascular smooth muscle cell function. NOTCH3 variants are the leading cause of hereditary cerebral small vessel disease (SVD). While monoallelic cysteine-involving missense variants in NOTCH3 are well-studied in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), patients with biallelic variants in NOTCH3 are extremely rare and not well characterised. METHODS: In this study, we present clinical and genetic data from 25 patients with biallelic NOTCH3 variants and conduct a literature review of another 25 cases (50 patients in total). Brain magnetic resonance imaging (MRI) were analysed by expert neuroradiologists to better understand the phenotype associated with biallelic NOTCH3 variants. FINDINGS: Our systematic analyses verified distinct genotype-phenotype correlations for the two types of biallelic variants in NOTCH3. Biallelic loss-of-function variants (26 patients) lead to a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Conversely, patients with biallelic cysteine-involving missense variants (24 patients) fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. White matter lesion volume is comparable between patients with biallelic cysteine-involving missense variants and individuals with CADASIL. Notably, monoallelic carriers of loss-of-function variants are predominantly asymptomatic, with only a few cases reporting nonspecific headaches. INTERPRETATION: We propose a NOTCH3-SVD classification depending on dosage and variant type. This study not only expands our knowledge of biallelic NOTCH3 variants but also provides valuable insight into the underlying mechanisms of the disease, contributing to a more comprehensive understanding of NOTCH3-related SVD. FUNDING: The Wellcome Trust, the MRC.

The First Reported Case of Ocular Syphilis in an Iranian Patient.

Purpose: To report the first case of ocular syphilis in an Iranian patient and discuss its diagnostic challenges. Case Report: A man in his mid-70s presented with progressive bilateral visual and auditory decline. He had previously lived in a Southeast Asian country for 10 years. Prior steroid therapies entailed no inflammation subsidence. His visual acuity at presentation was light perception OU. Funduscopic findings included severe vitritis, severe optic atrophy, diffuse retinal vascular occlusion, and diffuse retinal atrophy OU. Angiography demonstrated diffuse areas of retinal and choriocapillaris atrophy with no active choroiditis. Scaly cutaneous lesions were noted on his palms and soles - atypical findings of secondary syphilis. Serum analysis revealed an underlying syphilis infection. The cerebrospinal fluid sample was reactive to anti-syphilis antibodies, securing a neurosyphilis diagnosis. Two weeks of antibiotic therapy resulted in cutaneous lesions resolution and relative visual improvement despite extensive baseline retinal atrophic damage. Conclusion: Ocular syphilis can mimic numerous ocular inflammatory scenarios. In cases of ocular inflammation that is unresponsive to steroids, reconsidering alternative diagnoses, especially infections with the highest clinical relevance, is necessary. We stress the importance of acquiring patients' sexual history, regardless of cultural barriers and the rarity of the entity in some regions.

Multiple sclerosis and lower urinary tract symptoms: A survey of prevalence, characteristic and urological evaluations.

Objective: Most multiple sclerosis patients have urological complications such as lower urinary tract symptoms. This study was conducted to evaluate the prevalence of these symptoms and whether they result in a urological evaluation. Methods: A cross-sectional study of 517 multiple sclerosis patients at Tehran's referral multiple sclerosis center and neurology clinics between 2018 and 2022 was performed. Data were collected through interviews after patients completed informed consent forms. Urological examinations, including urine analysis and ultrasonography, were evaluated as final assessments. The data were analyzed using descriptive and inferential statistical tests in Statistical Package for Social Science. Results: Among all participants, the prevalence of lower urinary tract symptoms was 73% (n = 384), with urgency (44.8% n = 232) being the most common symptom. The prevalence of intermittency was significantly higher among women (p = 0.004). There was no gender-significant difference in terms of the prevalence of other symptoms (p > 0.050). Lower urinary tract symptoms were significantly correlated with age, clinical course, disease duration, and disability (p < 0.001). Additionally, 37.3% and 18.7% of patients with lower urinary tract symptoms, as well as 17.9% and 37.5% of patients with multiple sclerosis attacks, respectively, had undergone urine analysis and ultrasonography. Conclusion: Multiple sclerosis patients rarely undergo urological evaluations during the course of their disease. Proper assessment is essential as these symptoms are among the most detrimental manifestations of this disease.

Follow-up of 25 patients with treatable ataxia: A comprehensive case series study.

Autosomal recessive cerebellar ataxias are a group of heterogeneous early-onset progressive disorders that some of them are treatable. We performed a 4-year follow-up for 25 patients who had treatable ataxia. According to our study, patients would benefit from early detection of treatable ataxia, close observation, and follow-up.

The effect of low-dose naltrexone on quality of life of patients with multiple sclerosis: a randomized placebo-controlled trial.

BACKGROUND: Low-dose naltrexone (LDN) may promote psychological well-being as well as generalized health especially in autoimmune disorders. The objective of this study is to assess the effect of LDN on the Quality of Life (QoL) of patients with relapsing-remitting and secondary progressive multiple sclerosis (MS) using the scales and composite scores of the MSQoL-54 questionnaire. METHODS: A 17-week randomized, double-blind, placebo-controlled, parallel-group, crossover-design clinical trial was conducted in two universities. A total of 96 adult patients aged between 15 and 65 years with relapsing-remitting (RR) or secondary progressive (SP) clinically definite MS with disease duration longer than 6 months enrolled into the study. The primary outcome of the study was comparison of the scores of physical and mental health by conducting independent t-test of the results obtained in the middle and at the end of study between the two groups. RESULTS: Variables including presence of pain, energy, emotional well-being, social, cognitive, and sexual functions, role limitation due to physical and emotional problems, health distress, and overall QoL did not show any meaningful statistically difference between the two groups. Factor analysis revealed that health perception scores were statistically different between the groups before starting, in the middle, and at the end of the study. CONCLUSION: The study clearly illustrates that LDN is a relatively safe therapeutic option in RRMS and SPMS but its efficacy is under question and probably a long duration trial is needed in the future.

Whole exome sequencing revealed a novel dystrophin-related protein-2 (DRP2) deletion in an Iranian family with symptoms of polyneuropathy.

OBJECTIVES: Charcot-Marie Tooth disease (CMT) is one of the main inherited causes of motor and sensory neuropathies with variable expressivity and age-of onset. Although more than 70 genes have been identified for CMT, more studies are needed to discover other genes involved in CMT. Introduction of whole exome sequencing (WES) to capture all the exons may help to find these genes. MATERIALS AND METHODS: Here, we tried to find the genetic cause of the neuropathy in two Iranian brothers using WES. Blood sample was collected from probands and their family members to extract the genomic DNA. The extracted DNA from one of the affected case was subjected for WES. The variant calls were filtered to reveal the pathogenic variant. Presence of the candidate mutation was confirmed using Sanger sequencing. The pathogenic potential of the variant was examined using in silico software. Using ClustalW multiple alignment, the presence of variant in conserved domain of protein was investigated. The parent and another affected boy were also checked for presence of the variant using PCR-sequencing. RESULTS: The obtained data presented a novel TTC del mutation in CDS 738 of dystrophin related protein 2 (DRP2) gene, which was validated by sequencing. The variant was located in a conserved domain of DRP2 protein and predicted as pathogenic. Two affected boys were hemizygous for the mutation and received the mutation from mother. CONCLUSION: Here, we provided the evidence for the contribution of DRP2 in CMT. Also, the symptoms shed light on molecular aspect of this genetically heterogeneous disease.

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.

Genotype-Phenotype Correlations in Charcot-Marie-Tooth Disease Due to MTMR2 Mutations and Implications in Membrane Trafficking.

Charcot-Marie-Tooth type 4 (CMT4) is an autosomal recessive severe form of neuropathy with genetic heterogeneity. CMT4B1 is caused by mutations in the myotubularin-related 2 (MTMR2) gene and as a member of the myotubularin family, the MTMR2 protein is crucial for the modulation of membrane trafficking. To enable future clinical trials, we performed a detailed review of the published cases with MTMR2 mutations and describe four novel cases identified through whole-exome sequencing (WES). The four unrelated families harbor novel homozygous mutations in MTMR2 (NM_016156, Family 1: c.1490dupC; p.Phe498IlefsTer2; Family 2: c.1479+1G>A; Family 3: c.1090C>T; p.Arg364Ter; Family 4: c.883C>T; p.Arg295Ter) and present with CMT4B1-related severe early-onset motor and sensory neuropathy, generalized muscle atrophy, facial and bulbar weakness, and pes cavus deformity. The clinical description of the new mutations reported here overlap with previously reported CMT4B1 phenotypes caused by mutations in the phosphatase domain of MTMR2, suggesting that nonsense MTMR2 mutations, which are predicted to result in loss or disruption of the phosphatase domain, are associated with a severe phenotype and loss of independent ambulation by the early twenties. Whereas the few reported missense mutations and also those truncating mutations occurring at the C-terminus after the phosphatase domain cause a rather mild phenotype and patients were still ambulatory above the age 30 years. Charcot-Marie-Tooth neuropathy and Centronuclear Myopathy causing mutations have been shown to occur in proteins involved in membrane remodeling and trafficking pathway mediated by phosphoinositides. Earlier studies have showing the rescue of MTM1 myopathy by MTMR2 overexpression, emphasize the importance of maintaining the phosphoinositides equilibrium and highlight a potential compensatory mechanism amongst members of this pathway. This proved that the regulation of expression of these proteins involved in the membrane remodeling pathway may compensate each other's loss- or gain-of-function mutations by restoring the phosphoinositides equilibrium. This provides a potential therapeutic strategy for neuromuscular diseases resulting from mutations in the membrane remodeling pathway.

Association of G/C (rs638405) Polymorphism in ß-secretase Gene with Alzheimer's Disease.

BACKGROUND: Alzheimer's Disease (AD) is a neurodegenerative disorder, which is the most common cause of dementia in the elderly. Accumulation of ß-amyloid plaques outside neurons is the most important pathological hallmark of AD, which is produced by cleavage of amyloid precursor protein by the Alzheimer's ß-secretase (BACE1). Since BACE1 is a key enzyme in the formation of ß-amyloid peptides, the purpose of this study was to assess the association between polymorphisms of G/C (rs638405) BACE1 gene with sporadic AD in Khuzestan, Isfahan and Fars provinces in Iran. METHODS: Genotypes were determined by the PCR-Restriction Fragment Length Polymorphism (PCR-RFLP) technique in two groups including 89 sporadic AD patients and 73 healthy subjects. RESULTS: The findings of the BACE1 G/C (rs638405) polymorphism revealed that there was no significant difference between AD patients and controls in men group; however, there was a weak difference in the frequency of CC genotype between patients and controls in women group (χ 2=3.333, df=1, p=0.068). CONCLUSION: The results of this study suggest that the G/C (rs638405) polymorphism of BACE1 gene might not be related with sporadic AD in Khuzestan, Isfahan and Fars provinces in Iran. However, our results do not support a genetic risk factor of this polymorphism for developing AD in male group of this study.

The influence of ethnicity on the characteristics of multiple sclerosis: a local population study between Persians and Arabs.

BACKGROUND: Based on previous studies, Iran is located in a low risk area in terms of multiple sclerosis (MS). The objective of this study was to determine and compare the incidence, prevalence and demographic characteristics of MS in two ethnic groups of Persian and Arab over the period spanning 2009 in the Khuzestan province, in the Southwest of Iran. METHODS: A cross-sectional case register study was conducted between January and August 2009. All cases in the region whom were referred to the MS society in the city of Ahwaz were participants in the study. The population data from the Iranian Bureau of Statistics were used to calculate the population at risk based on the 1996 and 2006 census data. RESULTS: A total of 696 patients were identified according to the McDonald criteria during the last 12 years of which 569 patients were Persian. In 2009 the total prevalence and incidence rates of MS were 16.28 and 2.20 per 100,000 individuals. Based on these values, the female to male ratios were 3.11. The Persians manifested more sensory signs and symptoms (40.2%) but motor deficits (19.1%) and cerebellar findings (18.2%) were seen as being more manifest in Arab individuals. The main difference was observed in the progressive types of MS in which 24.7% of the Arab patients showed progressive type symptoms as compared to 15.9% of the cases in the Persian population. CONCLUSION: According to this study the authors conclude that the prevalence and incidence of MS were higher in Persians; however progressive forms of MS with motor and cerebellar signs are more frequent in the Arab ethnic group.