Sahar Saleem

INTRODUCTION: Pathogenic variants in the PIEZO family member 2 () gene are known to cause Gordon syndrome (GS), Marden-Walker syndrome (MWS), and distal arthrogryposis type 5 (DA5). Out of these, MWS has a recognizable phenotype that can be discerned easily, but the distinction between GS and DA5 is less evident. Few children with pathogenic variants have been reported to show posterior fossa anomalies.

METHODS AND RESULTS: By candidate gene targeting guided by proper clinical evaluation and neuroimaging findings, a patient with classic MWS harboring a de novo novel variant (c.8237G>A, p.W2746*) in the C-terminal region of PIEZO2 was identified. In addition, another girl with the typical clinical features of GS is also described carrying the most prevalent reported variant (c.8057G>A, p.R2686H) in . The brain MRI of the 2 patients showed Dandy-Walker malformation (DWM). Diffusion tensor imaging visualized anteroposterior and downward aligned thin middle cerebellar peduncle. The association of DWM with arthrogryposis in the presence of variants remains quite interesting and provides more evidence that PIEZO2 plays a role in the development of hindbrain although the underlying mechanism remains unclear. Moreover, the 2 girls had distinct foot patterning in the form of shortening of the first and fifth toes.

CONCLUSION: Phenotype analysis and a comprehensive review of the literature strongly support the previously published data and corroborate the evidence that heterozygous related disorders represent a continuum with overlapping phenotypic features.

Seqenenre-Taa-II, The Brave, (c.1558-1553 BC) ruled Southern Egypt during the occupation of Egypt by the Hyksos. The mummy was physically examined and X-rayed in the 1960s, which showed severe head wounds that have prompted various theories about the circumstances of his death. We postulated that Computed Tomography (CT) study of Seqenenre-Taa-II's mummy would give insights into the circumstances of his death. We examined Seqenenre's mummy using CT and compared the findings with the archaeological literature as well as with five Asian weapons found in Tell-el-Dabaa. CT findings indicate that Seqenenre died in his forties. The mummies deformed hands suggest that the King was likely imprisoned with his hands tied. CT images provided detailed analysis of Seqenenre's previously reported injuries to the forehead, right supra-orbital, nose-right orbit, left chick, and skull base. This study revealed additional craniofacial fractures in the right lateral side of the skull that had been concealed by the embalmers beneath layers of material. Analysis of the morphology of the injuries enabled a better understanding of the mechanism of trauma, possible number of the attackers, and their relative position to the King. The size and shape of the fractures correlated well with the studied Hyksos weapons. The lethal attack was aimed at the King's face, likely in an attempt to disgrace him. Mummification of Seqenenre's body was limited to evisceration without brain removal. The desiccated brain is shifted to the left side of the skull. This may indicate that the King's dead body stayed on its left side for some time-long enough for decomposition start before the mummification began. This suggests that the King likely died at a location distant from the funeral place, possibly on a battlefield. The embalmers attempted to conceal the King's injuries; the methods used suggest that the mummification took place in a royal mummification workshop rather than in a poorly equipped location. CT findings of Seqenenre's mummy helped us to better understand the circumstances of his violent death. His death motivated his successors to continue the fight to unify Egypt and start The New Kingdom.

The mummy of King Amenhotep I (18th Dynasty c.1525-1504 BC) was reburied by the 21st Dynasty priests at Deir el-Bahari Royal Cache. In 1881 the mummy was found fully wrapped and was one of few royal mummies that have not been unwrapped in modern times. We hypothesized that non-invasive digital unwrapping using CT would provide insights on the physical appearance, health, cause of death, and mummification style of the mummy of King Amenhotep I. We examined the mummy with CT and generated two- and three-dimensional images for the head mask, bandages, and the virtually unwrapped mummy. CT enabled the visualization of the face of Amenhotep I who died around the age of 35 years. The teeth had minimal attrition. There was no CT evidence of pathological changes or cause of death. The body has been eviscerated a vertical left flank incision. The heart is seen in the left hemithorax with an overlying amulet. The brain has not been removed. The mummy has 30 amulets/jewelry pieces including a beaded metallic (likely gold) girdle. The mummy suffered from multiple postmortem injuries likely inflicted by tomb robbers that have been likely treated by 21st Dynasty embalmers. These included fixing the detached head and neck to the body with a resin-treated linen band; covering a defect in the anterior abdominal wall with a band and placing two amulets beneath; placement of the detached left upper limb beside the body and wrapping it to the body. The transversely oriented right forearm is individually wrapped, likely representing the original 18th Dynasty mummification and considered the first known New Kingdom mummy with crossed arms at the chest. The head mask is made of cartonnage and has inlaid stone eyes. The digital unwrapping of the mummy of Amenhotep I using CT sets a unique opportunity to reveal the physical features of the King non-invasively, understand the mummification style early in the 18th Dynasty, and the reburial intervention style by 21st Dynasty embalmers. This study may make us gain confidence in the goodwill of the reburial project of the Royal mummies by the 21st dynasty priests.

The mummy of King Amenhotep I (18th Dynasty c.1525-1504 BC) was reburied by the 21st Dynasty priests at Deir el-Bahari Royal Cache. In 1881 the mummy was found fully wrapped and was one of few royal mummies that have not been unwrapped in modern times. We hypothesized that non-invasive digital unwrapping using CT would provide insights on the physical appearance, health, cause of death, and mummification style of the mummy of King Amenhotep I. We examined the mummy with CT and generated two- and three-dimensional images for the head mask, bandages, and the virtually unwrapped mummy. CT enabled the visualization of the face of Amenhotep I who died around the age of 35 years. The teeth had minimal attrition. There was no CT evidence of pathological changes or cause of death. The body has been eviscerated a vertical left flank incision. The heart is seen in the left hemithorax with an overlying amulet. The brain has not been removed. The mummy has 30 amulets/jewelry pieces including a beaded metallic (likely gold) girdle. The mummy suffered from multiple postmortem injuries likely inflicted by tomb robbers that have been likely treated by 21st Dynasty embalmers. These included fixing the detached head and neck to the body with a resin-treated linen band; covering a defect in the anterior abdominal wall with a band and placing two amulets beneath; placement of the detached left upper limb beside the body and wrapping it to the body. The transversely oriented right forearm is individually wrapped, likely representing the original 18th Dynasty mummification and considered the first known New Kingdom mummy with crossed arms at the chest. The head mask is made of cartonnage and has inlaid stone eyes. The digital unwrapping of the mummy of Amenhotep I using CT sets a unique opportunity to reveal the physical features of the King non-invasively, understand the mummification style early in the 18th Dynasty, and the reburial intervention style by 21st Dynasty embalmers. This study may make us gain confidence in the goodwill of the reburial project of the Royal mummies by the 21st dynasty priests.

Patients lacking PYCR2, a mitochondrial enzyme that synthesizes proline, display postnatal degenerative microcephaly with hypomyelination. Here we report the crystal structure of the PYCR2 apo-enzyme and show that a novel germline p.Gly249Val mutation lies at the dimer interface and lowers its enzymatic activity. We find that knocking out Pycr2 in mice phenocopies the human disorder and depletes PYCR1 levels in neural lineages. In situ quantification of neurotransmitters in the brains of PYCR2 mutant mice and patients revealed a signature of encephalopathy driven by excessive cerebral glycine. Mechanistically, we demonstrate that loss of PYCR2 upregulates SHMT2, which is responsible for glycine synthesis. This hyperglycemia could be partially reversed by SHMT2 knockdown, which rescued the axonal beading and neurite lengths of cultured Pycr2 knockout neurons. Our findings identify the glycine metabolic pathway as a possible intervention point to alleviate the neurological symptoms of PYCR2-mutant patients.

OBJECTIVE: The goal of this study is to demonstrate the need for interdisciplinary consensus and inclusion of mummy radiology specialists in analyses of mummified remains.

MATERIALS: This study uses paleoimaging data for an ancient Egyptian mummy at the Museum of Human Anatomy "Filippo Civinini".

METHODS: This study demonstrates the benefit of evaluation of mummified remains in a multi-disciplinary interpretive team.

RESULTS: The authors propose a diagnosis of DISH, additional signs of undifferentiated spondyloarthropathy, and lumbarisation of S1.

CONCLUSIONS: The process of diagnosis by consensus is essential to the analysis of mummified remains, which are complexly altered through natural and anthropogenic processes in the millennia subsequent to the individual's death.

SIGNIFICANCE: Mummy paleoimaging and paleopathology lacks a unifying set of standards. We present an example of the value to be found in the multi-disciplinary diagnosis by consensus approach.

LIMITATIONS: We discuss numerous challenges to accurate and meaningful interpretation that radiography of mummified remains pose.

SUGGESTIONS FOR FURTHER RESEARCH: While the authors do not seek to impose any single set of standards, we do recommend a larger discussion on the topic of (culture-specific) standardisation in mummy paleoimaging and paleopathology. We further recommend the development of an international, multi-disciplinary panel of paleoimaging interpreters.

OBJECTIVE: To identify causes of the autosomal-recessive malformation, diencephalic-mesencephalic junction dysplasia (DMJD) syndrome.

METHODS: Eight families with DMJD were studied by whole-exome or targeted sequencing, with detailed clinical and radiological characterization. Patient-derived induced pluripotent stem cells were derived into neural precursor and endothelial cells to study gene expression.

RESULTS: All patients showed biallelic mutations in the nonclustered protocadherin-12 (PCDH12) gene. The characteristic clinical presentation included progressive microcephaly, craniofacial dysmorphism, psychomotor disability, epilepsy, and axial hypotonia with variable appendicular spasticity. Brain imaging showed brainstem malformations and with frequent thinned corpus callosum with punctate brain calcifications, reflecting expression of PCDH12 in neural and endothelial cells. These cells showed lack of PCDH12 expression and impaired neurite outgrowth.

INTERPRETATION: DMJD patients have biallelic mutations in PCDH12 and lack of protein expression. These patients present with characteristic microcephaly and abnormalities of white matter tracts. Such pathogenic variants predict a poor outcome as a result of brainstem malformation and evidence of white matter tract defects, and should be added to the phenotypic spectrum associated with PCDH12-related conditions. Ann Neurol 2018;84:646-655.