Sahar Saleem

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.

We describe six cases from three unrelated consanguineous Egyptian families with a novel characteristic brain malformation at the level of the diencephalic–mesencephalic junction. Brain magnetic resonance imaging demonstrated a dysplasia of the diencephalic–mesencephalic junction with a characteristic ‘butterfly’-like contour of the midbrain on axial sections. Additional imaging features included variable degrees of supratentorial ventricular dilatation and hypoplasia to complete agenesis of the corpus callosum. Diffusion tensor imaging showed diffuse hypomyelination and lack of an identifiable corticospinal tract. All patients displayed severe cognitive impairment, post-natal progressive microcephaly, axial hypotonia, spastic quadriparesis and seizures. Autistic features were noted in older cases. Talipes equinovarus, non-obstructive cardiomyopathy and persistent hyperplastic primary vitreous were additional findings in two families. One of the patients required shunting for hydrocephalus; however, this yielded no change in ventricular size suggestive of dysplasia rather than obstruction. We propose the term ‘diencephalic–mesencephalic junction dysplasia’ to characterize this autosomal recessive malformation.

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.

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.

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.