Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders.

The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Using exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with myristic acid alkyne (YnMyr) chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), aged 1-50 years, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%) and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%) and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%) and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each) as well as hypertrophy of the clava (24%) were common neuroimaging findings. Acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localization and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-myristoylation was similarly affected in acbd6-deficient zebrafish and X. tropicalis models, including Fus, Marcks and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders.

Does endometriosis increase susceptibility to COVID-19 infections? A case-control study in women of reproductive age.

BACKGROUND: In today's world, coronavirus disease 2019 (COVID-19) is the most critical health problem and research is continued on studying the associated factors. But it is not clear whether endometriosis increases the risk of COVID-19. METHODS: Women who referred to the gynecology clinic were evaluated and 507 women with endometriosis (case group) were compared with 520 women without endometriosis (control group). COVID-19 infection, symptoms, exposure, hospitalization, isolation, H1N1 infection and vaccination, and past medical history of the participants were recorded and compared between the groups using IBM SPSS Statistics for Windows version 21. RESULTS: Comparison between the groups represent COVID-19 infection in 3.2% of the case group and 3% of the control group (P = 0.942). The control group had a higher frequency of asymptomatic infection (95.7% vs. 94.5%; P < 0.001) and fever (1.6% vs. 0%; P = 0.004), while the frequency of rare symptoms was more common in the case group (P < 0.001). The average disease period was 14 days in both groups (P = 0.694). COVID-19 infection was correlated with close contact (r = 0.331; P < 0.001 in the case group and r = 0.244; P < 0.001 in the control group), but not with the history of thyroid disorders, H1N1 vaccination, traveling to high-risk areas, and social isolation (P > 0.05). CONCLUSION: Endometriosis does not increase the susceptibility to COVID-19 infections, but alters the manifestation of the disease. The prevalence of the disease may depend on the interaction between the virus and the individual's immune system but further studies are required in this regard.

A Preliminary Report on the Largest Ongoing Outbreak of Lead Toxicity in Iran.

No countrywide data exists on the patients' characteristics of lead exposure in Iran. We aimed to evaluate the demographic characteristics and blood lead level (BLL) of these patients in the country scale during five consecutive years, including the epidemic outbreak year (2016). Between 2014 and 2018, records of all patients who had referred to two reference laboratories in Tehran, Iran, to check BLL were evaluated. Of 58,642 patients, 48,589 were male. Mean age was 44.9 ± 20.7 years. Males had higher BLLs and were significantly older. Median BLL was 16 µg/dL (0.3 to 263 µg/dL). Median BLL was significantly higher in 45- to 60-year-old patients. The highest median BLL was reported in May 2016 confirming our records about the peak of the epidemic. Although the frequency of high BLL declined after 2016, it never returned to the measures before that. Considering the ongoing high prevalence of increased BLLs after 2016 and similar environmental and occupational exposures as before, lead-contaminated opium still seems to persist in the Iranian opium black market. Substitution of this lead-contaminated opium by Opioid Maintenance Therapy (OMT)-prescribed opium tincture is recommended.

Validation of a next generation sequencing panel for detection of hotspot cancer mutations in a clinical laboratory.

Recent advances in sequencing technologies have enabled us to scrutinize the versatile underlying mechanisms of cancer more precisely. However, adopting these new sophisticated technologies is challenging for clinical labs as it involves complex workflows, and requires validation for diagnostic purposes. The aim of this work is towards the analytical validation of a next generation sequencing (NGS) panel for cancer hotspot mutation analysis. Characterized formalin-fixed paraffin-embedded (FFPE) samples including biopsy specimens and cell-lines were examined by NGS methods utilizing the Ion Torrent™ Oncomine™ Focus DNA Assay and the PGM™ platform. Important parameters for somatic mutations including the threshold for differentiation of a positive and a negative result, coverage, sensitivity, specificity, and limit of detection (LoD) were analyzed. Variant calls with coverage of <100x were found to be inaccurate. The limit of detection for identifying hotspot mutations was determined to be 4.3%. The sensitivity and specificity of the method were 96.1% and 97.8% respectively. No statistically significant difference was found between different gene targets in terms of performance of hotspot frequency measurement for the subset tested. In every validation study, the number of samples, the manner of sample selection, and the number and type of variants play a role in the outcome. Therefore, these parameters should be assessed according to the clinical needs of each laboratory undertaking the validation.

H. pylori infection and reflux oesophagitis: a case-control study.

AIM: To examine the relationship between H. pylori and gastro-oesophageal reflux disease (GORD) in Iran. METHODS: In this study 51 GORD patients (referred to endoscopy at Taleghani hospital) were compared with 49 age-sex matched controls. Diagnosis of H. pylori was made by gastric mucosal biopsy and rapid urease test (positive if the result of one or both diagnostic methods was positive). Updated Sydney system was used to report histopathological changes. RESULTS: The frequency of H. pylori infection based on rapid urease test and histology was 88.2% (45) in patients and 77.6% (38) in controls, which showed no significant difference. The frequency of H. pylori infection was significantly higher in the antrum than in the corpus and cardia. The mean activity, inflammation, and gastritis scores were also higher in the antrum of patients than in the antrum of controls. The mean scores were significantly higher in the corpus of controls than in the corpus of patients. Diffuse active gastritis was observed in a significantly larger number of controls, while the frequency of diffuse chronic gastritis was higher in patients. There was no significant difference in the frequency of other histological findings between patients and controls. CONCLUSION: H. pylori infection cannot prevent GORD in this region.