Global developmental delay and intellectual disability in the era of genomics: Diagnosis and challenges in resource limited areas.

AIMS: To report the diagnostic yield of clinical singleton whole exome sequencing (WES) performed among a group of Jordanian children presenting with global developmental delay /intellectual disability (GDD/ID), discuss the underlying identified genetic disorders and the challenges encountered. PATIENTS AND METHODS: This retrospective medical record review study included 154 children who were diagnosed with GDD/ID at our clinic at Jordan University Hospital between 2016 and 2021, and whose diagnostic work up included WES. RESULTS: Consanguinity among parents was reported in 94/154 (61.0%) patients and history of other affected siblings in 35/154 (22.7%) patients. Pathogenic and likely pathogenic variants (solved cases) were reported in 69/154 (44.8%) patients, a variant of uncertain significance was reported in 54/154 (35.0%) and a negative result was reported in 31/154 (20.1%) cases. In the solved cases, autosomal recessive diseases were the most common (33/69; 47.8%). Metabolic disorders were identified in 20/69 (28.9%) patients, followed by developmental and epileptic encephalopathies (9/69; 13.0%) and MECP2 related disorders (7/69; 10.1%). Other single gene disorders were identified in 33/69; 47.8%) patients. CONCLUSION: This study had several limitations, as it was hospital-based and only including patients who were able to afford the test. Nevertheless, it yielded several important findings. In resource-limited countries, WES may be a reasonable approach. We discussed the challenges that clinicians meet in the context of shortage of resources.

Congenital muscle dystrophies: Role of singleton whole exome sequencing in countries with limited resources.

AIM: Identify the genetic determinants of congenital muscle dystrophy (CMD) in Jordanian children. METHODS: This prospective study included patients suspected to have CMD. Singleton whole-exome sequencing (WES) was performed as the first-tier diagnostic test. RESULTS: 44 patients were included: 27 boys and 17 girls. Consanguinity was reported in 32/44 (72.7%) patients, and a positive family history in 16/44 (36.3%) patients. WES uncovered pathogenic/ likely pathogenic variants in 19/44 (43.1%) patients, variants of uncertain significance (VUS) and negative results were identified in 15/44 (34.0%) and 10/44 (22.7%) patients respectively. Variants related to CMD were identified in 23/44 (52.2%) patients; pathogenic /likely pathogenic variants were identified in 12/23 (52.1%) and VUS in 11/23 (47.8%). The most common genes were related to basal membrane/extracellular proteins followed by genes related to alpha­dystroglycanopathies. We have identified a rare association of one family with one sibling affected by CMD and the other sibling with Duchenne muscle dystrophy. A history suggestive of perinatal insult was found in 6/23 (26.0%) patients necessitating a high index of suspicion as CMD may present as cerebral palsy mimickers.Several strong candidate VUSs were identified and need future second tier testing for confirmation. WES identified genes related to other neuromuscular and non neuromuscular disorders in 21/44 (47.7%) patients;7/21 were pathogenic/likely pathogenic and 14/21 (66.6%) were VUS. CONCLUSIONS: In countries with limited resources singleton WES could be considered the first tier diagnostic test to limit costs.

Think Melkersson-Rosenthal Syndrome: A Fissured Tongue With Facial Paralysis.

Melkersson-Rosenthal syndrome (MRS) was first described and named after E. Melkersson in 1928 and C. Rosenthal in 1931. MRS is a rare cause of recurrent facial nerve palsy and can manifest as facial paralysis, orofacial edema, and/or tongue fissuring. Presenting with the complete triad, it was scarcely reported in literature. However, the patient reported here had the complete triad. MRS should be considered when facial paralysis is recurrent or when it presents with orofacial edema, and/or tongue fissuring.

Atomoxetine improves hippocampal cell proliferation but not memory in Doxorubicin-treated adult male rats.

Atomoxetine (ATX) is a noradrenaline reuptake inhibitor used to treat Attention deficit hyperactive disorder (ADHD), or improve cognition in normal subjects. Cancer patients treated with systemic adjuvant chemotherapy have described experiencing deterioration in cognition. Doxorubicin (DOX, Adriamycin) is one of the anthracycline families used in chemotherapy, which has a deteriorating effect on both cognition and proliferation. The cognitive effects of ATX require inputs from the hippocampus. The aim of this study was to examine spatial memory and proliferation in the subgranular zone (SGZ) of the DG in adult Lister Hooded rats treated either alone or with a combination of Atomoxetine (30 mg kg-1  day-1 , six i.p. doses, one injection every other day) and Doxorubicin (DOX) ( 2 mg kg-1  day-1 , six i.p. doses, one injection every other day). Spatial memory was tested using the Novel location recognition (NLR) test, and proliferation of hippocampal cells was quantified using immunohistochemistry for the proliferative marker Ki67. Results showed that ATX treatment has improved the NLR task and increased cell proliferation in the SGZ of the DG, compared with saline-treated controls. Animals treated with DOX only showed deficits in NLR task, and co-administration of ATX along with DOX did not improve their performance. DOX chemotherapy caused a significant reduction in the number of proliferating cells in the SGZ of the DG compared with saline-treated controls. This reduction was reversed by co-administration of ATX. The above findings suggest that DOX can negatively affect both cell proliferation and memory and ATX co-administration improves proliferation, but not memory in the adult male rat hippocampus.