Outlining the Clinical Profile of TCIRG1 14 Variants including 5 Novels with Overview of ARO Phenotype and Ethnic Impact in 20 Egyptian Families.

TCIRG1 gene mutations underlie osteopetrosis, a rare genetic disorder impacting osteoclast function with consequent brittle bones prone to fracture, in spite of being characterized by increased bone density. The disorder is known to exhibit marked genetic heterogeneity, has no treatment, and is lethal in most instances. There are reports of ethnic variations affecting bone mineral density and variants' expression as diverse phenotypes even within individuals descending from the same pedigree. We herein focus on one of osteopetrosis's three types: the autosomal recessive malignant form (MIM 259700) (ARO) that is almost always associated with severe clinical symptoms. We reviewed the results of about 1800 Egyptian exomes and we did not detect similar variants within our Egyptian dataset and secondary neurological deficit. We studied twenty Egyptian families: sixteen ARO patients, ten carrier parents with at least one ARO affected sib, and two fetuses. They were all subjected to thorough evaluation and TCIRG1 gene sequencing. Our results of twenty-eight individuals descending from twenty Egyptian pedigrees with at least one ARO patient, expand the phenotype as well as genotype spectrum of recessive mutations in the TCIRG1 gene by five novel pathogenic variants. Identifying TCIRG1 gene mutations in Egyptian patients with ARO allowed the provision of proper genetic counseling, carrier detection, and prenatal diagnosis starting with two families included herein. It also could pave the way to modern genomic therapeutic approaches.

Reference Values of Cerebral Artery Diameters of the Anterior Circulation by Digital Subtraction Angiography: A Retrospective Study.

A threshold-based classification of cerebral vasospasm needs reference values for intracranial vessel diameters on digital subtraction angiography (DSA). We aimed to generate adjusted reference values for this purpose by retrospectively analyzing angiograms and potential influencing factors on vessel diameters. Angiograms of the anterior circulation were evaluated in 278 patients aged 18−81 years. The vessel diameters of 453 angiograms (175 bilateral) were gathered from nine defined measuring sites. The effect sizes of physical characteristics (i.e., body weight and height, body mass index, gender, age, and cranial side) and anatomical variations were calculated with MANOVA. Segments bearing aneurysms were excluded for the calculation of reference values. Adjusted vessel diameters were calculated via linear regression analysis of the vessel diameter data. Vessel diameters increased with age and body height. Male and right-sided vessels were larger in diameter. Of the anatomical variations, only the hypoplastic/aplastic A1 segment had a significant influence (p < 0.05) on values of the anterior cerebral artery and the internal carotid artery with a small effect size (|ω2| > 0.01) being excluded from the reference values. We provide gender-, age-, and side-adjusted reference values and nomograms of arterial vessel diameters in the anterior circulation.

The Supratrochlear Artery Sign-A New Piece in the Puzzle of Cerebral Vasospasm.

BACKGROUND: Cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH) has been extensively investigated, but the impact of collateralization remains unclear. We investigated the predictive value of collateral activation for delayed cerebral ischemia (DCI)-related infarctions and functional outcome. METHODS: Data from 43 patients with CVS (January 2014 to August 2021) were evaluated for the angiographic presence of leptomeningeal and ophthalmic collaterals (anterior falcine artery (AFA), supratrochlear artery (STA), dorsal nasal artery (DNA)) on internal carotid artery angiograms. Vasospasm-related infarction and the modified Rankin Scale (mRS) score after six months were chosen as the endpoints. RESULTS: 77% of the patients suffered from DCI-related infarctions. In 233 angiograms (at hospitalization, before spasmolysis, after six months), positive vessel signs were observed in 31 patients for STA, 35 for DNA, and 31 for AFA. The STA sign had the highest positive (84.6%) and negative (85.7%) predictive value for unfavorable outcome (mRS 4-6) in patients aged ≥50 years. DNA and AFA signs were not meaningful predictors for either endpoint. Leptomeningeal collaterals showed a positive Pearson's correlation with the STA sign in 87.5% (p = 0.038) without providing any prediction for either endpoint. CONCLUSIONS: The STA sign is associated with clinical outcome in patients with CVS after SAH aged ≥50 years, and was correlated with the occurrence of leptomeningeal collaterals.

Cervical intradural extramedullary cavernous malformation as a rare cause of subarachnoid hemorrhage without spinal dysfunction: illustrative case.

BACKGROUND: Intradural extramedullary cavernoma is a very rare lesion of the spinal cord, especially of the cervical spine. Its clinical presentation can vary with symptoms of sensory or motor deficits and even with symptoms of subarachnoid hemorrhage (SAH). OBSERVATIONS: The authors present a case of a 45-year-old man with SAH with prolonged neck pain and increasing headache confirmed by lumbar puncture. Head computed tomography revealed only discrete blood deposits in the right frontal and biparietal lobes. The finding of pan-cerebral angiography was negative for the cause of bleeding. Spinal magnetic resonance imaging revealed an intradural extramedullary mass lesion at cervical level C5-6. The finding of subsequent cervical angiography was negative. The diagnosis of a cavernous malformation was confirmed histopathologically after surgery. The cavernoma was completely removed, and full recovery of the initial symptoms was achieved. LESSONS: Spinal lesions should be considered in the diagnostic work-up for SAH with excluded origin of bleeding in cranial neuroimaging. An intradural extramedullary cavernous malformation is an extremely rare entity in the differential diagnosis of SAH, and surgical resection is the treatment of choice to prevent further bleeding and neurological deficits.

Nimodipine vs. Milrinone - Equal or Complementary Use? A Retrospective Analysis.

Background: Cerebral vasospasm (CVS) continues to account for high morbidity and mortality in patients surviving the initial aneurysmal subarachnoid hemorrhage (SAH). Nimodipine is the only drug known to reduce delayed cerebral ischemia (DCI), but it is believed not to affect large vessel CVS. Milrinone has emerged as a promising option. Our retrospective study focused on the effectiveness of the intra-arterial application of both drugs in monotherapy and combined therapy. Methods: We searched for patients with aneurysmal SAH, angiographically confirmed CVS, and at least one intra-arterial pharmacological angioplasty. Ten defined vessel sections on angiograms were assessed before and after vasodilator infusion. The improvement in vessel diameters was compared to the frequency of DCI-related cerebral infarction before hospital discharge and functional outcome reported as the modified Rankin Scale (mRS) score after 6 months. Results: Between 2014 and 2021, 132 intra-arterial interventions (144 vascular territories, 12 bilaterally) in 30 patients were analyzed for this study. The vasodilating effect of nimodipine was superior to milrinone in all intradural segments. There was no significant intergroup difference concerning outcome in mRS (p = 0.217). Only nimodipine or the combined approach could prevent DCI-related infarction (both 57.1%), not milrinone alone (87.5%). Both drugs induced a doubled vasopressor demand due to blood pressure decrease, but milrinone alone induced tachycardia. Conclusions: The monotherapy with intra-arterial nimodipine was superior to milrinone. Nimodipine and milrinone may be used complementary in an escalation scheme with the administration of nimodipine first, complemented by milrinone in cases of severe CVS. Milrinone monotherapy is not recommended.

Standardized Classification of Cerebral Vasospasm after Subarachnoid Hemorrhage by Digital Subtraction Angiography.

BACKGROUND: During the last decade, cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) was a current research focus without a standardized classification in digital subtraction angiography (DSA). This study was performed to investigate a device-independent visual cerebral vasospasm classification for endovascular treatment. METHODS: The analyses are DSA based rather than multimodal. Ten defined points of intracranial arteries were measured in 45 patients suffering from cerebral vasospasm after SAH at three time points (hospitalization, before spasmolysis, control after six months). Mathematical clustering of vessel diameters was performed to generate four objective grades for comparison. Six interventional neuroradiologists in two groups scored 237 DSAs after a new visual classification (grade 0-3) developed on a segmental pattern of vessel contraction. For the second group, a threshold-based criterion was amended. RESULTS: The raters had a reproducibility of 68.4% in the first group and 75.2% in the second group. The complementary threshold-based criterion increased the reproducibility by about 6.8%, while the rating deviated more from the mathematical clustering in all grades. CONCLUSIONS: The proposed visual classification scheme of cerebral vasospasm is suitable as a standard grading procedure for endovascular treatment. There is no advantage of a threshold-based criterion that compensates for the effort involved. Automated vessel analysis is superior to compare inter-group results in research settings.

Prenatal diagnosis of mucopolysaccharidoses type II by two-dimensional electrophoresis and mass spectrometry in amniotic fluid.

AIM: To introduce a quantitative determination of heparan sulfate and dermatan sulfate by mass spectrometry and to compare it with two-dimensional electrophoresis of the glycosaminoglycans in the amniotic fluid for the prenatal diagnosis of mucopolysaccharidoses type II (MPS II). METHODS: Thirty pregnancies each with single fetus were subjected to amniocentesis at 16 weeks: 10 with a previously affected MPS II infant and 20 as controls. Prenatal diagnosis was done by both mass spectrometry two two-dimensional electrophoresis. RESULTS: Two-dimensional electrophoresis showed four affected with MPS II and six unaffected fetuses. Mass spectrometry verified these results. CONCLUSION: Two-dimensional electrophoresis of the glycosaminoglycans in amniotic fluid is a good qualitative method and mass spectrometry is a new accurate quantitative method for prenatal diagnosis of MPS II. Quantitative determination of glycosaminoglycans in amniotic fluid by mass spectrometry is both rapid and accurate. Prenatal diagnosis is recommended for at risk pregnancies and mass spectrometry offers speed and quantitation.

Genetic Implications in High-Risk Pregnancy and Its Outcome: A 2-Year Study.

OBJECTIVE: The aim of this study is to evaluate high-risk pregnant females' offspring as regard the presence of any medical condition, hereditary disorder, or major anomaly as well as to document parental sociodemographic characteristics and compliance with follow-up schedules of fetal medicine and clinical genetic clinics. STUDY DESIGN: This prospective 2-year cohort study of neonates and infants reported the referral indications, investigations, and diagnoses obtained through prenatal and postnatal examinations. It also reported their parental follow-up vigilance. RESULTS: Of the 811 infants of high risk females referred 460 (56.7%) came for assessment. Mean parental consanguinity and endogamy were 67 and 71.3%, respectively. All pregnant mothers underwent first-trimester biochemical testing (plasma protein-A, α-fetoprotein [AFP], human chorionic gonadotropin [hCG]) and serial ultrasound examinations. Seventy mothers needed second-trimester biochemical testing (AFP, hCG, and estriol). Sixty-two mothers underwent amniocentesis where G-banding karyotype, fluorescence in situ hybridization and targeted molecular testing for the specific gene mutation of single gene disorders were conducted according to suspected disorders. High quality fetal ultrasound was performed when brain malformations were suspected, while 16 fetuses required brain MRI examination. Mean age of newborns at first examination was 26.5 days. They were grouped according to the maternal indication for referral. Upon examination, 18 neonates had confirmed congenital malformations/genetic disorders. Five of them were diagnosed prenatally. In four other fetuses with single gene disorder, the molecular diagnosis of their affected siblings was not established prior to this pregnancy; thus, prenatal diagnosis was not possible. The remaining nine cases were diagnosed postnatally. CONCLUSION: Parental consanguinity and endogamy were increased among high-risk pregnancies. Public awareness about potential adverse effects of consanguineous marriages and the importance of genetic testing are imperative. A structured multidisciplinary team of specialists in fetal medicine, clinical genetics, and neonatology provides good genetic services. Expansion and financial support of these services are urgently required. KEY POINTS: · A multidisciplinary team provides good genetic services in high-risk pregnancies.. · Parental consanguinity and endogamy are increased among high-risk pregnancies.. · Increased public awareness about genetic testing importance and financial support are imperative..

A multicenter cohort study of early complications after cranioplasty: results of the German Cranial Reconstruction Registry.

OBJECTIVE: Cranioplasty (CP) is a crucial procedure after decompressive craniectomy and has a significant impact on neurological improvement. Although CP is considered a standard neurosurgical procedure, inconsistent data on surgery-related complications after CP are available. To address this topic, the authors analyzed 502 patients in a prospective multicenter database (German Cranial Reconstruction Registry) with regard to early surgery-related complications. METHODS: Early complications within 30 days, medical history, mortality rates, and neurological outcome at discharge according to the modified Rankin Scale (mRS) were evaluated. The primary endpoint was death or surgical revision within the first 30 days after CP. Independent factors for the occurrence of complications with or without surgical revision were identified using a logistic regression model. RESULTS: Traumatic brain injury (TBI) and ischemic stroke were the most common underlying diagnoses that required CP. In 230 patients (45.8%), an autologous bone flap was utilized for CP; the most common engineered materials were titanium (80 patients [15.9%]), polyetheretherketone (57 [11.4%]), and polymethylmethacrylate (57 [11.4%]). Surgical revision was necessary in 45 patients (9.0%), and the overall mortality rate was 0.8% (4 patients). The cause of death was related to ischemia in 2 patients, diffuse intraparenchymal hemorrhage in 1 patient, and cardiac complications in 1 patient. The most frequent causes of surgical revision were epidural hematoma (40.0% of all revisions), new hydrocephalus (22.0%), and subdural hematoma (13.3%). Preoperatively increased mRS score (OR 1.46, 95% CI 1.08-1.97, p = 0.014) and American Society of Anesthesiologists Physical Status Classification System score (OR 2.89, 95% CI 1.42-5.89, p = 0.003) were independent predictors of surgical revision. Ischemic stroke, as the underlying diagnosis, was associated with a minor rate of revisions compared with TBI (OR 0.18, 95% CI 0.06-0.57, p = 0.004). CONCLUSIONS: The authors have presented class II evidence-based data on surgery-related complications after CP and have identified specific preexisting risk factors. These results may provide additional guidance for optimized treatment of these patients.

Molecular diagnosis in recessive pediatric neurogenetic disease can help reduce disease recurrence in families.

BACKGROUND: The causes for thousands of individually rare recessive diseases have been discovered since the adoption of next generation sequencing (NGS). Following the molecular diagnosis in older children in a family, parents could use this information to opt for fetal genotyping in subsequent pregnancies, which could inform decisions about elective termination of pregnancy. The use of NGS diagnostic sequencing in families has not been demonstrated to yield benefit in subsequent pregnancies to reduce recurrence. Here we evaluated whether genetic diagnosis in older children in families supports reduction in recurrence of recessive neurogenetic disease. METHODS: Retrospective study involving families with a child with a recessive pediatric brain disease (rPBD) that underwent NGS-based molecular diagnosis. Prenatal molecular testing was offered to couples in which a molecular diagnosis was made, to help couples seeking to prevent recurrence. With this information, families made decisions about elective termination. Pregnancies that were carried to term were assessed for the health of child and mother, and compared with historic recurrence risk of recessive disease. RESULTS: Between 2010 and 2016, 1172 families presented with a child a likely rPBD, 526 families received a molecular diagnosis, 91 families returned to the clinic with 101 subsequent pregnancies, and 84 opted for fetal genotyping. Sixty tested negative for recurrence for the biallelic mutation in the fetus, and all, except for one spontaneous abortion, carried to term, and were unaffected at follow-up. Of 24 that genotyped positive for the biallelic mutation, 16 were electively terminated, and 8 were carried to term and showed features of disease similar to that of the older affected sibling(s). Among the 101 pregnancies, disease recurrence in living offspring deviated from the expected 25% to the observed 12% ([95% CI 0·04 to 0·20], p = 0·011). CONCLUSIONS: Molecular diagnosis in an older child, coupled with prenatal fetal genotyping in subsequent pregnancies and genetic counselling, allows families to make informed decisions to reduce recessive neurogenetic disease recurrence.

Combination of Human Amniotic Fluid Derived-Mesenchymal Stem Cells and Nano-hydroxyapatite Scaffold Enhances Bone Regeneration.

BACKGROUND: Human amniotic fluid-derived stem cells (hAF-MSCs) have a high proliferative capacity and osteogenic differentiation potential in vitro. The combination of hAF-MSCs with three-dimensional (3D) scaffold has a promising therapeutic potential in bone tissue engineering and regenerative medicine. Selection of an appropriate scaffold material has a crucial role in a cell supporting and osteoinductivity to induce new bone formation in vivo. AIM: This study aimed to investigate and evaluate the osteogenic potential of the 2nd-trimester hAF-MSCs in combination with the 3D scaffold, 30% Nano-hydroxyapatite chitosan, as a therapeutic application for bone healing in the induced tibia defect in the rabbit. SUBJECT AND METHODS: hAF-MSCs proliferation and culture expansion was done in vitro, and osteogenic differentiation characterisation was performed by Alizarin Red staining after 14 & 28 days. Expression of the surface markers of hAF-MSCs was assessed using Flow Cytometer with the following fluorescein-labelled antibodies: CD34-PE, CD73-APC, CD90-FITC, and HLA-DR-FITC. Ten rabbits were used as an animal model with an induced defect in the tibia to evaluate the therapeutic potential of osteogenic differentiation of hAF-MSCs seeded on 3D scaffold, 30% Nano-hydroxyapatite chitosan. The osteogenic differentiated hAF-MSCs/scaffold composite system applied and fitted in the defect region and non-seeded scaffold was used as control. The histopathological investigation was performed at 2, 3, & 4 weeks post-transplantation and scanning electron microscope (SEM) was assessed at 2 & 4 weeks post-transplantation to evaluate the bone healing potential in the rabbit tibia defect. RESULTS: Culture and expansion of 2nd-trimester hAF-MSCs presented high proliferative and osteogenic potential in vitro. Histopathological examination for the transplanted hAF-MSCs seeded on the 3D scaffold, 30% Nano-hydroxyapatite chitosan, demonstrated new bone formation in the defect site at 2 & 3 weeks post-transplantation as compared to the control (non-seeded scaffold). Interestingly, the scaffold accelerated the osteogenic differentiation of AF-MSCs and showed complete bone healing of the defect site as compared to the control (non-seeded scaffold) at 4 weeks post-transplantation. Furthermore, the SEM analysis confirmed these findings. CONCLUSION: The combination of the 2nd-trimester hAF-MSCs and 3D scaffold, 30% Nano-hydroxyapatite chitosan, have a therapeutic perspective for large bone defect and could be used effectively in bone tissue engineering and regenerative medicine.

Delayed Stroke after Aneurysm Treatment with Flow Diverters in Small Cerebral Vessels: A Potentially Critical Complication Caused by Subacute Vasospasm.

Flow diversion (FD) is a novel endovascular technique based on the profound alteration of cerebrovascular hemodynamics, which emerged as a promising minimally invasive therapy for intracranial aneurysms. However, delayed post-procedural stroke remains an unexplained concern. A consistent follow-up-regimen has not yet been defined, but is required urgently to clarify the underlying cause of delayed ischemia. In the last two years, 223 patients were treated with six different FD devices in our center. We identified subacute, FD-induced segmental vasospasm (SV) in 36 patients as a yet unknown, delayed-type reaction potentially compromising brain perfusion to a critical level. Furthermore, 86% of all patients revealed significant SV approximately four weeks after treatment. In addition, 56% had SV with 25% stenosis, and 80% had additional neointimal hyperplasia. Only 13% exhibited SV-related high-grade stenosis. One of those suffered stroke due to prolonged SV, requiring neurocritical care and repeated intra-arterial (i.a.) biochemical angioplasty for seven days to prevent territorial infarction. Five patients suffered newly manifested, transient hemicrania accompanying a compensatorily increased ipsilateral leptomeningeal perfusion. One treated vessel obliterated permanently. Hence, FD-induced SV is a frequent vascular reaction after FD treatment, potentially causing symptomatic ischemia or even stroke, approximately one month post procedure. A specifically early follow-up-strategy must be applied to identify patients at risk for ischemia, requiring intensified monitoring and potentially anti-vasospastic treatment.

A Clear Mystery: Recognizing Lipomatosis of the Nerve.

Lipomatosis of the nerve (LN) commonly presents with neurologic dysfunction due to massive fibro-fatty enlargement of the peripheral nerves. It is uniquely associated with adipose proliferation in the subcutaneous tissue and muscle in the innervated territory, along with osseous abnormalities. Herein, we present the case of a 56-year-old woman who presented with severe right ulnar distribution pain involving the medial forearm and hand (9/10 on a numerical rating scale), declining right-hand strength, movement-dependent hypoesthesias, paresthesias, and a pronounced claw deformity of the right hand with intrinsic atrophy. Electrodiagnostic studies demonstrated pronounced fibrillations, decreased voluntary activation, and minimal collateral reinnervation in the abductor digiti minimi and abductor pollicis brevis, consistent with dysfunction of the lower trunk of the right brachial plexus. Magnetic resonance imaging (MRI) and computed tomography (CT) of the brachial plexus were interpreted as a tumor on the right supra- and infraclavicular brachial plexus. At surgery, the brachial plexus was embedded in relatively tight connective tissue with a typical lipoma posteriorly. The lipoma was resected, and the plexus was explored extensively. This case is the 10th report of LN involving the brachial plexus and demonstrated the cardinal features of LN. It provides insight into the pattern of lesions associated with innervation by LN.

Osteogenic Differentiation Potential of Human Bone Marrow and Amniotic Fluid-Derived Mesenchymal Stem Cells in Vitro & in Vivo.

BACKGROUND: Cell therapies offer a promising potential in promoting bone regeneration. Stem cell therapy presents attractive care modality in treating degenerative conditions or tissue injuries. The rationale behind this is both the expansion potential of stem cells into a large cell population size and its differentiation abilities into a wide variety of tissue types, when given the proper stimuli. A progenitor stem cell is a promising source of cell therapy in regenerative medicine and bone tissue engineering. AIM: This study aimed to compare the osteogenic differentiation and regenerative potentials of human mesenchymal stem cells derived from human bone marrow (hBM-MSCs) or amniotic fluid (hAF-MSCs), both in vitro and in vivo studies. SUBJECTS AND METHODS: Human MSCs, used in this study, were successfully isolated from two human sources; the bone marrow (BM) and amniotic fluid (AF) collected at the gestational ages of second or third trimesters. RESULTS: The stem cells derived from amniotic fluid seemed to be the most promising type of progenitor cells for clinical applications. In a pre-clinical experiment, attempting to explore the therapeutic application of MSCs in bone regeneration, Rat lumbar spines defects were surgically created and treated with undifferentiated and osteogenically differentiated MSCs, derived from BM and second trimester AF. Cells were loaded on gel-foam scaffolds, inserted and fixed in the area of the surgical defect. X-Ray radiography follows up, and histopathological analysis was done three-four months post- operation. The transplantation of AF-MSCs or BM-MSCs into induced bony defects showed promising results. The AF-MSCs are offering a better healing effect increasing the likelihood of achieving successful spinal fusion. Some bone changes were observed in rats transplanted with osteoblasts differentiated cells but not in rats transplanted with undifferentiated MSCs. Longer observational periods are required to evaluate a true bone formation. The findings of this study suggested that the different sources; hBM-MSCs or hAF-MSCs exhibited remarkably different signature regarding the cell morphology, proliferation capacity and osteogenic differentiation potential. CONCLUSIONS: AF-MSCs have a better performance in vivo bone healing than that of BM-MSCs. Hence, AF derived MSCs is highly recommended as an alternative source to BM-MSCs in bone regeneration and spine fusion surgeries. Moreover, the usage of gel-foam as a scaffold proved as an efficient cell carrier that showed bio-compatibility with cells, bio-degradability and osteoinductivity in vivo.

Association between biomarkers of vitamin B12 status and the risk of neural tube defects.

AIM: The aim of this study was to evaluate the association between vitamin B12 and its biomarkers and the risk of neural tube defects. METHODS: A total of 120 pregnant Egyptian women were included in the study. They were classified into two groups. Group A consisted of 50 women with neural tube defects in current pregnancy or with a history in previous pregnancies, and Group B consisted of 70 women with no history of neural tube defects in previous pregnancies or in the current pregnancy. All women were subjected to ultrasound anomaly scan and serum analysis of vitamin B12, homocysteine (Hcy), methyl malonic acid (MMA) and active vitamin B12 concentrations. Receiver operating characteristic curve analysis was used to determine the best cut-off values of vitamin B12. RESULTS: Serum levels of vitamin B12 were decreased in Neural tube defects (NTDs) cases compared to controls (2.736 vs 3.091 ng/mL; P = 0.0015), while Hcy and MMA concentrations were elevated (18.39 vs 13.95 µmol/L; P = 0.0008 and 263 vs 229.7 µmol/L; P = 0.003, respectively). Active vitamin B12 reduction was not statistically significant (96.8 vs 99.36 pmol/L; P = 0.8013). The optimal cut-off value of vitamin B12, 2.9 ng/mL, is the best threshold to expect neural tube defects, with a sensitivity of 60% and specificity of 74.29%. CONCLUSION: Low vitamin B12 is a risk factor for having a fetus with neural tube defects. The monitoring of MMA and Hcy levels might be important in understanding and following cases with neural tube defects. Adding vitamin B12 to folic acid may help to decrease the incidence of neural tube defects in the Egyptian population.

Identification of a novel homozygous ALX4 mutation in two unrelated patients with frontonasal dysplasia type-2.

We report two unrelated boys with frontonasal dysplasias type-2 (FND-2) who shared an identical novel homozygous ALX4 mutation c.291delG (p.Q98Sfs*83). Both patients presented with a large skull defect but one had bilateral parietal meningocele-like cysts that lie along with the bony defect and increased in size with age. Scalp alopecia, hypertelorism, and clefted alae nasi were also detected in both of them. Furthermore, impalpable gonads were noted, being unilateral in one and bilateral in the other. Neuroimaging showed small dysplastic occipital lobes with dysgyria and midline subarachnoid cyst. Additional dysplastic corpus callosum and small cerebellar vermis were observed in one patient. Parietal foramina were noted in the parents of one patient. Our findings highlight the dosage effect of ALX4 and underscore the challenges of prenatal genetic counseling. Further, the indirect role of ALX4 in the development of the occipital lobe and posterior fossa is discussed.

Changes in Binding of [(123)I]CLINDE, a High-Affinity Translocator Protein 18 kDa (TSPO) Selective Radioligand in a Rat Model of Traumatic Brain Injury.

After traumatic brain injury (TBI), secondary injuries develop, including neuroinflammatory processes that contribute to long-lasting impairments. These secondary injuries represent potential targets for treatment and diagnostics. The translocator protein 18 kDa (TSPO) is expressed in activated microglia cells and upregulated in response to brain injury and therefore a potential biomarker of the neuroinflammatory processes. Second-generation radioligands of TSPO, such as [(123)I]CLINDE, have a higher signal-to-noise ratio as the prototype ligand PK11195. [(123)I]CLINDE has been employed in human studies using single-photon emission computed tomography to image the neuroinflammatory response after stroke. In this study, we used the same tracer in a rat model of TBI to determine changes in TSPO expression. Adult Sprague-Dawley rats were subjected to moderate controlled cortical impact injury and sacrificed at 6, 24, 72 h and 28 days post surgery. TSPO expression was assessed in brain sections employing [(123)I]CLINDE in vitro autoradiography. From 24 h to 28 days post surgery, injured animals exhibited a marked and time-dependent increase in [(123)I]CLINDE binding in the ipsilateral motor, somatosensory and parietal cortex, as well as in the hippocampus and thalamus. Interestingly, binding was also significantly elevated in the contralateral M1 motor cortex following TBI. Craniotomy without TBI caused a less marked increase in [(123)I]CLINDE binding, restricted to the ipsilateral hemisphere. Radioligand binding was consistent with an increase in TSPO mRNA expression and CD11b immunoreactivity at the contusion site. This study demonstrates the applicability of [(123)I]CLINDE for detailed regional and quantitative assessment of glial activity in experimental models of TBI.

Expanding the mutation and clinical spectrum of Roberts syndrome.

Roberts syndrome and SC phocomelia syndrome are rare autosomal recessive genetic disorders representing the extremes of the spectrum of severity of the same condition, caused by mutations in ESCO2 gene. We report three new patients with Roberts syndrome from three unrelated consanguineous Egyptian families. All patients presented with growth retardation, mesomelic shortening of the limbs more in the upper than in the lower limbs and microcephaly. Patients were subjected to clinical, cytogenetic and radiologic examinations. Cytogenetic analysis showed the characteristic premature separation of centromeres and puffing of heterochromatic regions. Further, sequencing of the ESCO2 gene identified a novel mutation c.244_245dupCT (p.T83Pfs*20) in one family besides two previously reported mutations c.760_761insA (p.T254Nfs*27) and c.764_765delTT (p.F255Cfs*25). All mutations were in homozygous state, in exon 3. The severity of the mesomelic shortening of the limbs and craniofacial anomalies showed variability among patients. Interestingly, patient 1 had abnormal skin hypopigmentation. Serial fetal ultrasound examinations and measurements of long bones diagnosed two affected fetuses in two of the studied families. A literature review and case comparison was performed. In conclusion, we report a novel ESCO2 mutation and expand the clinical spectrum of Roberts syndrome.

Fetal brain disruption sequence versus fetal brain arrest: A distinct autosomal recessive developmental brain malformation phenotype.

The term fetal brain disruption sequence (FBDS) was coined to describe a number of sporadic conditions caused by numerous external disruptive events presenting with variable imaging findings. However, rare familial occurrences have been reported. We describe five patients (two sib pairs and one sporadic) with congenital severe microcephaly, seizures, and profound intellectual disability. Brain magnetic resonance imaging (MRI) revealed unique and uniform picture of underdeveloped cerebral hemispheres with increased extraxial CSF, abnormal gyral pattern (polymicrogyria-like lesions in two sibs and lissencephaly in the others), loss of white matter, dysplastic ventricles, hypogenesis of corpus callosum, and hypoplasia of the brainstem, but hypoplastic cerebellum in one. Fetal magnetic resonance imaging (FMRI) of two patients showed the same developmental brain malformations in utero. These imaging findings are in accordance with arrested brain development rather than disruption. Molecular analysis excluded mutations in potentially related genes such as NDE1, MKL2, OCLN, and JAM3. These unique clinical and imaging findings were described before among familial reports with FBDS. However, our patients represent a recognizable phenotype of developmental brain malformations, that is, apparently distinguishable from either familial microhydranencephaly or microlissencephaly that were collectively termed FBDS. Thus, the use of the umbrella term FBDS is no longer helpful. Accordingly, we propose the term fetal brain arrest to distinguish them from other familial patients diagnosed as FBDS. The presence of five affected patients from three unrelated consanguineous families suggests an autosomal-recessive mode of inheritance. The spectrum of fetal brain disruption sequence is reviewed.

Transient but not permanent benefit of neuronal progenitor cell therapy after traumatic brain injury: potential causes and translational consequences.

BACKGROUND: Numerous studies have reported a beneficial impact of neural progenitor cell transplantation on functional outcome after traumatic brain injury (TBI) during short and medium follow-up periods. However, our knowledge regarding long-term functional effects is fragmentary while a direct comparison between local and systemic transplantation is missing so far. OBJECTIVES: This study investigated the long-term (12 week) impact of human fetal neuronal progenitor cell (hNPC) transplantation 24 h after severe TBI in rats. METHODS: Cells were either transplanted stereotactically (1 × 10(5)) into the putamen or systemically (5 × 10(5)) via the tail vein. Control animals received intravenous transplantation of vehicle solution. RESULTS: An overall functional benefit was observed after systemic, but not local hNPC transplantation by area under the curve analysis (p < 0.01). Surprisingly, this effect vanished during later stages after TBI with all groups exhibiting comparable functional outcomes 84 days after TBI. Investigation of cell-mediated inflammatory processes revealed increasing microglial activation and macrophage presence during these stages, which was statistically significant after systemic cell administration (p < 0.05). Intracerebral hNPC transplantation slightly diminished astrogliosis in perilesional areas (p < 0.01), but did not translate into a permanent functional benefit. No significant effects on angiogenesis were observed among the groups. CONCLUSION: Our results suggest the careful long-term assessment of cell therapies for TBI, as well as to identify potential long-term detrimental effects of such therapies before moving on to clinical trials. Moreover, immunosuppressive protocols, though widely used, should be rigorously assessed for their applicability in the respective setup.