Sahar N. Saleem

Defective Wnt-dependent cerebellar midline fusion in a mouse model of Joubert syndrome

The ciliopathy Joubert syndrome is marked by cerebellar vermis hypoplasia, a phenotype for which the pathogenic mechanism is unclear. To investigate Joubert syndrome pathogenesis, we have examined mice with mutated Ahi1, the first identified Joubert syndrome–associated gene. These mice show cerebellar hypoplasia with a vermis-midline fusion defect early in development. This defect is concomitant with expansion of the roof plate and is also evident in a mouse mutant for another Joubert syndrome–associated gene, Cep290. Furthermore, fetal magnetic resonance imaging (MRI) of human subjects with Joubert syndrome reveals a similar midline cleft, suggesting parallel pathogenic mechanisms. Previous evidence has suggested a role for Jouberin (Jbn), the protein encoded by Ahi1, in canonical Wnt signaling. Consistent with this, we found decreased Wnt reporter activity at the site of hemisphere fusion in the developing cerebellum of Ahi1-mutant mice. This decrease was accompanied by reduced proliferation at the site of fusion. Finally, treatment with lithium, a Wnt pathway agonist, partially rescued this phenotype. Our findings implicate a defect in Wnt signaling in the cerebellar midline phenotype seen in Joubert syndrome that can be overcome with Wnt stimulation.

The molar tooth sign A new Joubert syndrome and related cerebellar disorders classification system tested in Egyptian families

Joubert syndrome and related cerebellar disorders (JSRD) are a group of recessive congenital ataxia conditions usually showing neonatal hypotonia, dysregulated breathing rhythms, oculomotor apraxia, and mental retardation. The pathognomonic finding in JSRD is the unique molar tooth sign (MTS) on brain imaging. There is a tremendously broad spectrum of signs and symptoms mainly including kidney, retina, and liver disease, along with polydactyly and facial dysmorphisms. Here we propose a new diagnostic classification within JSRD that includes four major subtypes. To test this classification, we performed a systematic recruitment and genetic evaluation from a single referral center in Egypt. Thirteen families were identified, four showed evidence of linkage to one of the four known genetic loci, three showed novel AHI1 mutations, and nine were excluded from known loci. Each family could be classified into one of the four subtypes. This classification may thus be useful in the evaluation of patients with JSRD. GLOSSARY: BUN = blood urinary nitrogen; COACH = cerebellar vermis hypo/aplasia-oligophrenia-ataxia-ocular coloboma-hepatic fibrosis; CORS = cerebello-oculo-renal syndrome; CVH = cerebellar vermis hypoplasia; DAS = Dekaban-Arima syndrome; DWM = Dandy-Walker malformation; JSRD = Joubert syndrome and related cerebellar disorders; LCA = Leber congenital amaurosis; lod = logarithm of odds score; MKS = Meckel-Gruber syndrome; MTS = molar tooth sign; NPH = nephronophthisis; NRC = National Research Center; OFD-VI = oro-facio-digital syndrome type VI; PCH = pontocerebellar hypoplasia; RHO = rhombencephalosynapsis; SLS = Senior-Loken syndrome.

Fetal MRI: An approach to practice: A review.

MRI has been increasingly used for detailed visualization of the fetus in utero as well as pregnancy structures. Yet, the familiarity of radiologists and clinicians with fetal MRI is still limited. This article provides a practical approach to fetal MR imaging. Fetal MRI is an interactive scanning of the moving fetus owed to the use of fast sequences. Single-shot fast spin-echo (SSFSE) T2-weighted imaging is a standard sequence. T1-weighted sequences are primarily used to demonstrate fat, calcification and hemorrhage. Balanced steady-state free-precession (SSFP), are beneficial in demonstrating fetal structures as the heart and vessels. Diffusion weighted imaging (DWI), MR spectroscopy (MRS), and diffusion tensor imaging (DTI) have potential applications in fetal imaging. Knowing the developing fetal MR anatomy is essential to detect abnormalities. MR evaluation of the developing fetal brain should include recognition of the multilayered-appearance of the cerebral parenchyma, knowledge of the timing of sulci appearance, myelination and changes in ventricular size. With advanced gestation, fetal organs as lungs and kidneys show significant changes in volume and T2-signal. Through a systematic approach, the normal anatomy of the developing fetus is shown to contrast with a wide spectrum of fetal disorders. The abnormalities displayed are graded in severity from simple common lesions to more complex rare cases. Complete fetal MRI is fulfilled by careful evaluation of the placenta, umbilical cord and amniotic cavity. Accurate interpretation of fetal MRI can provide valuable information that helps prenatal counseling, facilitate management decisions, guide therapy, and support research studies.

Magnetic resonance imaging in fetal anomalies: What does it add to 3D and 4D US?

OBJECTIVE The objective of our study is to evaluate the contribution of adding MRI findings to sonographic data when assessing fetal anomalies and to determine how this addition may affect the management of pregnancy. STUDY DESIGN We prospectively examined 26 fetuses who had sonographically suspected congenital anomalies over a period of 1 year. 2D/3D and 4D ultrasound, Doppler and magnetic resonant imaging was done for all patients. MRI was done within 1 week following US examination. The maternal age range was 18-39 years. The gestational age range was 15-38 weeks (mean age=29 weeks). Ultrasound and magnetic resonance findings were compared together. RESULTS We reported different types of congenital anomalies including eight cases of isolated central nervous system anomalies, four abdominal, five musculoskeletal anomalies, seven cases of renal anomalies and two cases of Meckel Gruber syndrome. MRI and sonography showed concordant findings in 18 cases. MRI changed the diagnosis in five cases and provided additional information in three cases. Ultrasound was superior to magnetic resonance imaging in three cases. CONCLUSION Our results showed that fetal MR imaging can be used as a complementary modality to US in diagnosing fetal abnormality in which US findings are inconclusive or equivocal.

Revisiting the harem conspiracy and death of Ramesses III: anthropological, forensic, radiological, and genetic study.

Objective To investigate the true character of the harem conspiracy described in the Judicial Papyrus of Turin and determine whether Ramesses III was indeed killed. Design Anthropological, forensic, radiological, and genetic study of the mummies of Ramesses III and unknown man E, found together and taken from the 20th dynasty of ancient Egypt (circa 1190-1070 BC). Results Computed tomography scans revealed a deep cut in Ramesses III’s throat, probably made by a sharp knife. During the mummification process, a Horus eye amulet was inserted in the wound for healing purposes, and the neck was covered by a collar of thick linen layers. Forensic examination of unknown man E showed compressed skin folds around his neck and a thoracic inflation. Unknown man E also had an unusual mummification procedure. According to genetic analyses, both mummies had identical haplotypes of the Y chromosome and a common male lineage. Conclusions This study suggests that Ramesses III was murdered during the harem conspiracy by the cutting of his throat. Unknown man E is a possible candidate as Ramesses III’s son Pentawere.

Microcephaly, malformation of brain development and intracranial calcification in sibs: Pseudo-TORCH or a new syndrome†

We report on five sibs affected by congenital microcephaly, growth retardation, sloping forehead, bitemporal grooving and micrognathia. Generalized tonic‐clonic seizures started very early in life. Postnatal brain computerized tomography (CT) presented cortical band‐like calcification, calcification of basal ganglia and brain stem while brain magnetic resonance imaging (MRI) revealed abnormal gyral pattern, marked loss of white matter, dysplastic ventricles, polymicrogyria, hypogenesis of corpus callosum and cerebellar hypoplasia. No abnormalities of the internal organs, eye, or skeleton were found to be associated with this syndrome. Fetal Magnetic resonance imaging helped reaching the diagnosis in utero in one patient. Three patients died in the first years of life while the others within days after birth preceded by high fever and status epilepticus. These patients present many overlapping features with pseudo TORCH syndrome, however, the imaging findings are quite different. We propose that the distinct pattern in these sibs constitutes genetic disorder of microcephaly, developmental brain malformation and intracranial calcification of likely autosomal recessive inheritance.

Fetal MRI in the evaluation of fetuses referred for sonographically suspected neural tube defects (NTDs): impact on diagnosis and management decision

IntroductionWe hypothesized that magnetic resonance imaging (MRI) can assess fetuses with sonographically (ultrasonography (US))-suspected neural tube defects (NTD) that might influence their diagnoses and management decision.MethodsInstitutional review board approval and informed consents were obtained to perform MRI for 19 fetuses referred with US-suspected NTD. Prenatal imaging findings were correlated with management decision, postnatal clinical, postnatal imaging, and pathology.ResultsPrenatal MRI correctly ruled out US diagnosis of cephalocele in a fetus. In the other 18 fetuses, MRI detected detailed topography and contents of NTD sacs in five, added central nervous system (CNS) abnormalities that were not apparent on US in three, and confirmed non-CNS findings in three fetuses. MRI changed diagnosis of 3/19 fetuses (15.8%), caused minor change in diagnosis of 5/19 (26.3%), and did not influence US diagnosis of 11/19 fetuses (57.9%). MRI findings changed/modified management decision in 21% of the fetuses.ConclusionFetal MRI is an important adjunct to US in assessing NTD. It can identify topography and contents of sacs, add CNS and non-CNS findings, and influence management decision.

Mummified Daughters of King Tutankhamun: Archeologic and CT Studies

OBJECTIVE The purpose of this study was to use MDCT to examine two mummies found in the tomb of King Tutankhamun to estimate their gestational ages at mummification, to determine the mummification method, and to investigate the congenital deformities of one of the mummies that had been suspected at previous medical examinations. MATERIALS AND METHODS MDCT was performed on the mummies of the daughters of King Tutankhamun (article numbers 317a and 317b), and the images were reconstructed and subjected to forensic imaging analysis. RESULTS The gestational ages at mummification of mummies 317a and 317b were estimated to be approximately 24.7 and 36.78 weeks. The skeletal congenital anomalies of mummy 317b suggested at past radiographic analysis were ruled out. CONCLUSION The results of this study may set a precedent for use of CT and forensic image analysis in the study of ancient mummified fetuses.

Variability in Brain Treatment During Mummification of Royal Egyptians Dated to the 18th–20th Dynasties: MDCT Findings Correlated With the Archaeologic Literature

OBJECTIVE The objective of our study was to use MDCT to study brain treatment and removal (excerebration) as part of mummification of royal Egyptian mummies dated to the 18th to early 20th Dynasties and to correlate the imaging findings with the archaeologic literature. MATERIALS AND METHODS As part of an MDCT study of the Royal Ancient Egyptian Mummies Project, we analyzed CT images of the heads of 12 mummies dated to circa 1493-1156 BC (18th to early 20th Dynasties). We reconstructed and analyzed CT images for the presence of cranial defects, brain remnants, intracranial embalming materials, and nasal packs. We compared the CT findings of mummies dated to the 18th Dynasty with those dated to the 19th to early 20th Dynasties. RESULTS The Akhenaten mummy was excluded because of extensive postmortem skull fractures. CT showed that no brain treatment was offered to three mummies (Thutmose I, II, and III) who dated to the early 18th Dynasty and was offered to the eight mummies who dated later. The route of excerebration was transnasal in eight mummies; an additional suspected route was via a parietal defect. CT showed variable appearances of the intracranial contents. There were larger volumes of cranial packs and more variability in the appearances of the cranial packs in the royal mummies dated to the 19th to 20th Dynasties than in those dated to the 18th Dynasty. CONCLUSION MDCT shows variations in brain treatment during mummification of royal Egyptian mummies (18th-20th Dynasties). This study sets a template for future CT studies of the heads of ancient Egyptian mummies and focuses on the key elements of cranial mummification in this ancient era.

Fetal Magnetic Resonance Imaging (MRI) A Tool for a Better Understanding of Normal and Abnormal Brain Development

Knowledge of the anatomy of the developing fetal brain is essential to detect abnormalities and understand their pathogenesis. Capability of magnetic resonance imaging (MRI) to visualize the brain in utero and to differentiate between its various tissues makes fetal MRI a potential diagnostic and research tool for the developing brain. This article provides an approach to understand the normal and abnormal brain development through schematic interpretation of fetal brain MR images. MRI is a potential screening tool in the second trimester of pregnancies in fetuses at risk for brain anomalies and helps in describing new brain syndromes with in utero presentation. Accurate interpretation of fetal MRI can provide valuable information that helps genetic counseling, facilitates management decisions, and guides therapy. Fetal MRI can help in better understanding the pathogenesis of fetal brain malformations and can support research that could lead to disease-specific interventions.