Molecular characterization of a large cohort of mucopolysaccharidosis patients: Iran Mucopolysaccharidosis RE-diagnosis study (IMPRESsion).

Mucopolysaccharidoses (MPSs) are rare, heterogeneous inborn errors of metabolism (IEM) diagnosed through a combination of clinical, biochemical, and genetic investigations. The aim of this study was molecular characterization of the largest cohort of Iranian MPS patients (302 patients from 289 unrelated families), along with tracking their ethnicity and geographical origins. 185/289 patients were studied using an IEM-targeted NGS panel followed by complementary Sanger sequencing, which led to the diagnosis of 154 MPS patients and 5 non-MPS IEMs (diagnostic yield: 85.9%). Furthermore, 106/289 patients who were referred with positive findings went through reanalysis and confirmatory tests which confirmed MPS diagnosis in 104. Among the total of 258 MPS patients, 225 were homozygous, 90 harbored novel variants, and 9 had copy number variations. MPS IV was the most common type (34.8%) followed by MPS I (22.7%) and MPS VI (22.5%). Geographical origin analysis unveiled a pattern of distribution for frequent variants in ARSB (c.430G>A, c.962T>C [p.Leu321Pro], c.281C>A [p.Ser94*]), GALNS (c.319G>A [p.Ala107Thr], c.860C>T [p.Ser287Leu], c.1042A>G [p.Thr348Ala]), and IDUA (c.1A>C [p.Met1Leu], c.1598C>G [p.Pro533Arg], c.1562_1563insC [p.Gly522Argfs*50]). Our extensive patient cohort reveals the genetic and geographic landscape of MPS in Iran, which provides insight into genetic epidemiology of MPS and can facilitate a more cost-effective, time-efficient diagnostic approach based on the region-specific variants.

Preimplantation High-Resolution HLA Sequencing Using Next Generation Sequencing.

Hematopoietic stem cell transplantation (SCT) is the only therapeutic option in a number of heritable hematologic disorders and hematologic cancers. Many parents and families fail to find an HLA-identical donor for their affected family member. In such cases, conceiving for a "savior baby" remains the only option, especially in countries without access to national registries. By means of next generation sequencing (NGS) techniques, in a single experiment on single-cell products of in vitro fertilization, a healthy HLA-identical embryo can be implanted in the uterus of a concerned mother. The patient can therefore benefit from cord blood SCT along with confirming that the fetuses are not suffering from the heritable disorder. This study is an attempt to study the feasibility of preimplantation HLA sequencing on single blastomeres using NGS. Two couples who had previously undergone preimplantation genetic diagnosis of ß-thalassemia and their overall 10 embryos were studied and their 5 HLA loci were typed in high resolution through multiple displacement amplification and NGS of single cells. For 88.9% of the 90 HLA alleles, conclusive HLA typing in 4 digit sets was made. HLA alleles were typed; 1 ambiguity in the allelic group and 4 ambiguities in the protein level were observed that were then unraveled by haplotype analysis. Amplification efficiency was 93.3% with an allele drop-out (ADO) rate of 22.2% (6 alleles dropped from a maximum of 27 possible ADOs). In this study the feasibility of a new method of preimplantation HLA sequencing via combining the state-of-the-art techniques used in single-cell whole genome amplification, preimplantation genetic diagnosis, and high-resolution HLA typing by NGS has been shown. This method can make preimplantation HLA sequencing a practicable technique in families desperate for an HLA-matched donor.

Re-Evaluating Risk Factors, Incidence, and Outcome of Aneurysmal and Non-Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVE: Subarachnoid hemorrhage (SAH) is one of the world's most life-threatening types of stroke. SAH can be classified into two main categories, aneurysmal (aSAH) and non-aneurysmal SAH (naSAH). In the present study, we aimed to prospectively evaluate SAH and its subcategories incidences, risk factors, complications, and outcomes in central Iran. METHODS: All SAH patients diagnosed between 2016 and 2020 were included in Isfahan SAH Registry. Demographic, clinical characteristics, incidence rates (based on age categories), and laboratory/imaging findings were collected and compared between aSAH and naSAH subgroups. Complications during hospital stay and outcomes were also analyzed. Binary logistic regression analysis was performed to investigate the predictors of aSAH versus naSAH. Kaplan-Meier curves and Cox regression were used to evaluate the survival probability. RESULTS: A total of 461 SAH patients were included through Isfahan SAH Registry. The SAH annual incidence rate was 3.11 per 100,000 person-years. aSAH had higher incidence rate than naSAH (2.08/100,000 vs. 0.9/100,000 person-years, respectively). In-hospital mortality was 18.2%. Hypertension (P = 0.003) and smoking (P = 0.03) were significantly associated with aSAH, whereas diabetes mellitus (P < 0.001) was more associated with naSAH. After Cox regression analysis, there were higher hazard ratios for reduced in-hospital survival in conditions including altered mental status, Glasgow Coma Scale ≤13, rebleeding, and seizures. CONCLUSIONS: This study provided an updated estimation of SAH and its subgroups incidences in central Iran. Risk factors for aSAH are comparable to the ones reported in the literature. It is noteworthy that diabetes mellitus was associated with a higher incidence of naSAH in our cohort.

Reversible Cerebral Vasoconstriction Syndrome and Multisystem Inflammatory Syndrome in Children With COVID-19.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) involves multiple organs and shows increased inflammatory markers. Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, several studies have reported the association between severe COVID-19 and MIS-C. Reversible cerebral vasoconstriction syndrome (RCVS) presents with thunderclap headaches and multifocal reversible vasoconstriction on imaging. RCVS is very rare in children. This article reports two cases of pediatric COVID-19 with severe MIS-C and clinical and imaging features indicative of RCVS. METHODS: Clinical, laboratory, and imaging data of the patients were reviewed. The diagnosis of RCVS was confirmed based on clinical symptomatology and brain magnetic resonance imaging findings. RESULTS: Two pediatric patients with clinical findings compatible with severe MIS-C and hemodynamic compromise presented to the hospital. During their hospitalization course, they developed thunderclap headaches and neurological deficits. Both were receiving vasoactive agents, intravenous immunoglobulin, and immunosuppressants. Imaging studies showed marked multifocal cerebral vasoconstriction in both cases and infarcts in one. The course and management of the patients will be presented. After controlling inflammation and elimination of triggers, both patients were ultimately symptom free upon discharge. Cerebral vasoconstriction had completely resolved on follow-up imaging. CONCLUSIONS: Although a variety of symptoms including headaches may be seen in pediatric COVID-19 patients with MIS-C, RCVS should be considered as a differential diagnosis in cases of thunderclap headache accompanied by neurological signs in these patients. Imaging findings and follow-up are also key in establishing the diagnosis.

Longitudinally extensive transverse myelitis as a sign of multisystem inflammatory syndrome following COVID-19 infection: A pediatric case report.

COVID-19 infection can cause inflammatory reactions that could involve several organs. In the pediatric population, Multi-System Inflammatory Syndrome in Children (MIS-C) has been reported as one of the consequences of COVID-19. We report a unique pediatric COVID-19 patient with MIS-C, associated with paralysis of the extremities. MRI showed abnormal signal in the cervical spinal cord compatible with transverse myelitis. Methylprednisolone and IVIG were administered, without significant symptom improvement. As a next step, Infliximab was tried for her, and she responded remarkably well to this treatment. Infliximab may be considered as a treatment option in COVID-19 patients with transverse myelitis.