Mitochondrial DNA depletion syndromes (MTDPS) are a group of rare genetic disorders caused by defects in multiple genes involved in mitochondrial DNA (mtDNA) maintenance. Among those, FBXL4 mutations result in the encephalomyopathic mtDNA depletion syndrome 13 (MTDPS13; OMIM #615471), which commonly presents as a combination of failure to thrive, neurodevelopmental delays, encephalopathy, hypotonia, and persistent lactic acidosis. We report here the case of a Lebanese infant presenting to us with profound neurodevelopmental delays, generalized hypotonia, facial dysmorphic features, and extreme emaciation. Whole-exome sequencing (WES) showed the girl as having MTDPS13 with an underlying FBXL4 missense mutation that has been previously reported only twice in unrelated individuals (c.1303C > T). Comprehensive literature search marked our patient as being the 94th case of MTDPS13 reported to date worldwide, and the first from Lebanon. We include at the end of this report a comprehensive mutation review table of all the pathological FBXL4 mutations reported in the literature, using it to highlight, for the first time, a possible founder effect of Arab origins to the disorder, being most prevalent in patients of Arab descent as shown in our mutation table. Finally, we provide a direct comparison of the disorder's clinical manifestations across two unrelated patients harboring the same disease-causing mutation as our patient, emphasizing the remarkable variability in genotype-to-phenotype correlation characteristic of the disease.

Biallelic variants of the gene encoding for the zinc-finger protein 142 (ZNF142) have recently been associated with intellectual disability (ID), speech impairment, seizures, and movement disorders in nine individuals from five families. In this study, we obtained phenotype and genotype information of 26 further individuals from 16 families. Among the 27 different ZNF142 variants identified in the total of 35 individuals only four were missense. Missense variants may give a milder phenotype by changing the local structure of ZF motifs as suggested by protein modeling; but this correlation should be validated in larger cohorts and pathogenicity of the missense variants should be investigated with functional studies. Clinical features of the 35 individuals suggest that biallelic ZNF142 variants lead to a syndromic neurodevelopmental disorder with mild to moderate ID, varying

Contactin-associated protein-like 2 (CNTNAP2) gene encodes for CASPR2, a presynaptic type 1 transmembrane protein, involved in cell–cell adhesion and synaptic interactions. Biallelic CNTNAP2 loss has been associated with “Pitt-Hopkins-like syndrome-1” (MIM#610042), while the pathogenic role of heterozygous variants remains controversial. We report 22 novel patients harboring mono- (n = 2) and bi-allelic (n = 20) CNTNAP2 variants and carried out a literature review to characterize the genotype–phenotype correlation. Patients (M:F 14:8) were aged between 3 and 19 years and affected by global developmental delay (GDD) (n = 21), moderate to profound intellectual disability (n = 17) and epilepsy (n = 21). Seizures mainly started in the first two years of life (median 22.5 months). Antiseizure medications were successful in controlling the seizures in about two-thirds of the patients. Autism spectrum disorder (ASD) and/or other neuropsychiatric comorbidities were present in nine patients (40.9%). Nonspecific midline brain anomalies were noted in most patients while focal signal abnormalities in the temporal lobes were noted in three subjects. Genotype–phenotype correlation was performed by also including 50 previously published patients (15 mono- and 35 bi-allelic variants). Overall, GDD (p < 0.0001), epilepsy (p < 0.0001), hyporeflexia (p = 0.012), ASD (p = 0.009), language impairment (p = 0.020) and severe cognitive impairment (p = 0.031) were significantly associated with the presence of biallelic versus monoallelic variants. We have defined the main features associated with biallelic CNTNAP2 variants, as severe cognitive impairment, epilepsy and behavioral abnormalities. We propose CASPR2-deficiency neurodevelopmental disorder as an exclusively recessive disease while the contribution of heterozygous variants is less likely to follow an autosomal dominant inheritance pattern.

Background: Sickle cell disease (SCD) is one of the most prevalent hemoglobinopathies in Lebanon, where 0.1% of the population are affected by the disease, with the highest prevalence in North Lebanon. SCD burden has not been well characterized in this patient population. Moreover, there is limited understanding of the factors associated with complications of SCD. We hereby report on characteristics, complications, treatments and survival of a SCD cohort treated at a comprehensive SCD referral clinic in North Lebanon. Methods: Data were extracted from the health records and electronic registry of 335 SCD patients treated at the comprehensive SCD clinic of Nini hospital, Tripoli, North Lebanon between 2009 and 2019. The study population consisted of referred and newly diagnosed patients. Patients were considered to be newly diagnosed with SCD if there was a gap of ≤ 60 days between SCD diagnosis date and their first clinic visit date. Patients were regularly seen in the clinic at intervals ranging from every 2 months to 1 year depending on their age and disease severity. Patient characteristics, complications, treatment choices, and mortality were evaluated during follow-up. Follow-up was defined as the time between SCD diagnosis and last visit to the clinic. Complications included vaso-occlusive crisis (VOC), acute splenic sequestration (ASS), stroke, dactylitis, joint necrosis, priapism, leg ulcers, sepsis, iron overload and mortality. VOC events, defined as the composite of pain and/or acute chest syndrome (ACS), were only reported if they resulted in a hospitalization. Since history of VOC events was not well documented among referred patients, VOC events were assessed among patients newly diagnosed at the clinic. Results: The mean age of the study population at SCD diagnosis was 2.9 years (standard deviation [SD]: 4.3), with 73.1% of patients diagnosed within 3 years of age. Mean age at first visit to the clinic was 8.6 years (SD 10.0). 159 (47.5%) patients were female. The most common genotypes were Hemoglobin SS (233 [69.6%]), Hemoglobin Beta-0 Thalassemia (62 [18.5%]), and Hemoglobin Beta + thalassemia (27 [8.1%]). The mean number of follow up years between SCD diagnosis date and latest visit date to the clinic was 13.7 (SD: 10.5). 132 (39.4%) patients were newly diagnosed at the time of their first visit to the clinic. The most frequently encountered SCD clinical events were pain (189 [56.4%]) followed by ACS (135 [40.3%]), ASS (115 [34.3%]) and joint necrosis (55 [16.4%]). The incidence of stroke, pulmonary hypertension, priapism, leg ulcers and sepsis was low (3.3%, 4.2%, 6.0%, 3.0% and 3.9%). Persistent splenomegaly beyond 6 years was seen in 57 (17%) patients, 36 (63.2%) of these patients were of SS genotype. 276 (82.4%) patients required at least one hospitalization during their follow-up. Among newly diagnosed patients, 63% experienced at least one VOC event that led to a hospitalization with a mean of 0.4 (SD: 0.6) hospitalized VOC events per patient per year. 15 (4.5%) patients died during follow-up. The most common cause of death was stroke (3 [20%]). 84 (25.1%) and 76 (22.7%) patients underwent a cholecystectomy and surgical splenectomy respectively, and 30 (9.0%) patients underwent both. 236 (70.5%) patients were treated with Hydroxyurea. The mean age at introduction of Hydroxyurea was 11.5 years (SD: 10.1) and median starting dose was 15.2 mgs/kg/day. 281 (84%) patients received at least one blood transfusion during their follow-up. 37 (11.0%) patients received iron chelation during their follow up. 3 (0.9%) patients underwent bone marrow transplant and were cured of their disease. Conclusion: This first SCD study from North Lebanon demonstrates that SCD burden in North Lebanon is significant. Despite the high disease burden and the low community resources in this region, survival rate of this SCD patient population is relatively high. This can be attributed to the young age at diagnosis, the close comprehensive follow-up and the regular parent/patient education. The low rate of stroke, priapism and leg ulcers in this population warrants further investigation via disease associated markers and genetic determinants. As for priapism, it may be underreported due to social stigma in a conservative country as Lebanon. Noteworthy, Iron overload is under recognized and sub optimally treated. The association between specific risk factors and disease complications will be further addressed. Disclosures Inati: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novonordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Global Blood Therapeutics: Research Funding. Kanakamedala:Novartis: Consultancy; Genesis Research: Employment. Pilipovic:Novartis Pharma AG: Employment, Equity Ownership. Sabah:Novartis: Employment.

PNPLA8, one of the calcium-independent phospholipase A2 enzymes, is involved in various physiological processes through the maintenance of membrane phospholipids. However, little is known about its role in brain development. Here, we report 12 individuals from 10 unrelated families with biallelic ultra-rare variants inPNPLA8presenting with a wide spectrum of clinical features ranging from developmental and epileptic-dyskinetic encephalopathy (DEDE) to progressive movement disorders and no phenotype depending on the variants and their positions. Complete loss of PNPLA8 was associated with the severe end of the spectrum, showing DEDE manifestations and congenital or progressive microcephaly. Using cerebral organoids generated from human induced pluripotent stem cells, we found that loss of PNPLA8 reduced the number of basal radial glial cells (bRGCs) and upper-layer neurons. By spatial transcriptomic analysis targeting apical radial glial cells (aRGCs), we found the downregulation of bRGC-related gene sets in patient-derived cerebral organoids. Lipidomic analysis revealed a decrease in the amount of lysophosphatidic acid, lysophosphatidylethanolamine, and phosphatidic acid, indicative of the disturbed phospholipid metabolism inPNPLA8knockout neural progenitor cells. Our data suggest that PNPLA8 has a critical role in the bRGC-mediated expansion of the developing human cortex by regulating the fate commitment of aRGCs.