Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome

Defective primary ciliogenesis or cilium stability forms the basis of human ciliopathies, including Joubert syndrome (JS), with defective cerebellar vermis development. We performed a high-content genome wide siRNA screen to identify genes regulating ciliogenesis as candidates for JS. We analyzed results with a supervised learning approach, using SYSCILIA gold standard, Cildb3.0, a centriole siRNA screen and the GTex project, identifying 591 likely candidates. Intersection of this data with whole exome results from 145 individuals with unexplained JS identified six families with predominantly compound heterozygous mutations in KIAA0586. A c.428del base deletion in 0.1% of the general population was found in trans with a second mutation in an additional set of 9 of 163 unexplained JS patients. KIAA0586 is an orthologue of chick Talpid3, required for ciliogenesis and sonic hedgehog signaling. Our results uncover a relatively high frequency cause for JS and contribute a list of candidates for future gene discoveries in ciliopathies

The shrunken, bright cerebellum: A characteristic MRI finding in congenital disorders of glycosylation type 1a

CDG-1a is an early-onset neurodegenerative disease with selective hindbrain involvement and highly variable clinical presentation. We retrospectively reviewed the clinical records and MR imaging studies of 5 children (3 boys and 2 girls aged 12 days to 2 years at presentation) with molecularly confirmed CDG-1a. The cerebellum was hypoplastic at presentation in 4 cases, progressive bulk loss involved the cerebellum and the pons in all cases, and the cerebellar cortex and subcortical white matter were hyperintense on T2-weighted and FLAIR images in all. We conclude that CDG-1a likely results from a combination of cerebellar hypoplasia and atrophy. Cerebellar volume loss with diffuse T2/FLAIR hyperintensity seems to be a peculiar association in the field of cerebellar atrophies, and may be useful to address the differential diagnosis

Steroids receptors immunohistochemical expression in different sites of endometriosis

Background: A better characterization of steroid intracrine pathways in endometriosis lesions may lead to a better understanding of the pathogenesis of the disease and insights on the mechanism of resistance to medical therapy. The study aims to evaluate the expression of steroid receptors in endometriosis lesions, including for the first-time androgen receptors, both in glandular and stromal tissue, and to describe the differences, in any, in receptor expression in the different subtypes. Basic procedures: This is a retrospective analysis of 76 specimens from 51 women, that underwent laparoscopic surgery for endometriosis at a tertiary hospital between 2015 and 2019. Immunohistochemical detections of estrogen, progesterone and androgen receptors positive cells was performed and the results described in terms of both density and intensity. The density and intensity scores were combined to obtain a final Histological Score (HS). Non-parametric Kruskal-Wallis test or Mann-Whitney U-test were used to compare continuous data, chi square test for categorical data. Main findings: Estrogen receptor \u3b1 expression was moderate/high in almost all specimens, regardless of the site. Samples from endometriomas presented lower progesterone receptor expression in the epithelium, compared to pelvic sites. Androgen receptor density was higher in stromal cells compared to epithelial cells and in pelvic sites compared to ovarian ones. Conclusions: The roles of nuclear receptors in endometriosis, including differences in their expression, could help in defining the pathogenesis of the disease and in explaining different responsivity to therapies. The intracrine regulation of steroids plays a relevant role in the metabolic and inflammatory pathogenetic paths of endometriosis: if better understood, its manipulation could be a relevant therapeutic target for treatment

The Shrunken, Bright Cerebellum: A Characteristic MRI Finding in Congenital Disorders of Glycosylation Type 1a

CDG-1a is an early-onset neurodegenerative disease with selective hindbrain involvement and highly variable clinical presentation. We retrospectively reviewed the clinical records and MR imaging studies of 5 children (3 boys and 2 girls aged 12 days to 2 years at presentation) with molecularly confirmed CDG-1a. The cerebellum was hypoplastic at presentation in 4 cases, progressive bulk loss involved the cerebellum and the pons in all cases, and the cerebellar cortex and subcortical white matter were hyperintense on T2-weighted and FLAIR images in all. We conclude that CDG-1a likely results from a combination of cerebellar hypoplasia and atrophy. Cerebellar volume loss with diffuse T2/FLAIR hyperintensity seems to be a peculiar association in the field of cerebellar atrophies, and may be useful to address the differential diagnosis

The shrunken, bright cerebellum: a characteristic MRI finding in congenital disorders of glycosylation type 1a.

SUMMARY: CDG-1a is an early-onset neurodegenerative disease with selective hindbrain involvement and highly variable clinical presentation. We retrospectively reviewed the clinical records and MR imaging studies of 5 children (3 boys and 2 girls aged 12 days to 2 years at presentation) with molecularly confirmed CDG-1a. The cerebellum was hypoplastic at presentation in 4 cases, progressive bulk loss involved the cerebellum and the pons in all cases, and the cerebellar cortex and subcortical white matter were hyperintense on T2-weighted and FLAIR images in all. We conclude that CDG-1a likely results from a combination of cerebellar hypoplasia and atrophy. Cerebellar volume loss with diffuse T2/FLAIR hyperintensity seems to be a peculiar association in the field of cerebellar atrophies, and may be useful to address the differential diagnosis. ABBREVIATIONS: BAEP ϭ brain stem auditory evoked potential; CA ϭ cerebellar atrophy; CDG ϭ congenital disorders of glycosylation; CH ϭ cerebellar hypoplasia; EEG ϭ electroencephalogram; ERG ϭ electroretinogram; mIns ϭ myo-inositol; NCV ϭ nerve conduction velocity; PMM ϭ phosphomannomutase; PRESS ϭ point-resolved spectroscopy sequence; sI ϭ scyllo-inositol; VEP ϭ visual-evoked potentials C DGs are genetically heterogeneous autosomal recessive disorders caused by abnormal glycosylation of N-linked oligosaccharides. CDG-1a (OMIM#212065), caused by mutation in the gene encoding PMM2, is the most common form. The clinical presentation and course are highly variable, ranging from severe infantile multisystem involvement to mild late-onset forms. 1 Muscular hypotonia, strabismus, and developmental delay are variably associated with dysmorphic features, abnormal subcutaneous fat distribution ("fat pads"), nipple retraction, feeding problems, and failure to thrive. Stroke-like episodes have also been reported. 3 Brain MR imaging studies have consistently shown a small cerebellum, variably designated as cerebellar hypoplasia, olivopontocerebellar hypoplasia, or cerebellar atrophy. 3-7 The purpose of this study is to describe the MR imaging findings on initial and follow-up studies in patients with CDG-1a and to identify suggestive MR imaging features that may prompt further diagnostic tests. Materials and Methods Institutional review board approval was not sought, as it is not required in our country for retrospective studies that do not involve patient identity disclosure. Five Italian children (3 males and 2 females, aged 12 days to 2 years at clinical presentation) with confirmed CDG-1a constitute the focus of this article. These patients were selected on the basis of a molecular genetic confirmation of the diagnosis and the availability of at least 1 MR imaging study for evaluation. We retrospectively reviewed their clinical, laboratory, electrophysiologic, and neurologic information. Laboratory investigations included routine blood work, analysis of transferrin by serum isoelectric focusing, and enzymatic analysis of PMM activity on skin fibroblasts. In all cases, molecular analysis of the PMM2 gene was performed according to standard techniques. NCV studies were performed on all patients; VEPs, ERGs, and EEGs were performed in 4, whereas BAEPs were performed in 3. A total of 9 brain MR imaging studies were performed in the 5 patients between 1991 and 2008; each patient underwent 2 MR imaging studies, except patient 2. The interval between the 2 MR imaging studies in individual patients ranged from 10 months to 14 years. Of the 9 MR imaging studies, 8 were performed with a 1.5T superconductive system (Intera Achieva; Philips, Best, the Netherlands) using an 8-channel parallel imaging head coil; these studies included 3-mm-thick sagittal T1-and T2-weighted images, 5-mm-thick axial T1-and T2-weighted images, and 4-mm-thick coronal T2-weighted and FLAIR images. Imaging parameters were as follows: TR 500 -670 ms, TE 12-25 ms, NEX 2, for T1 weighting; TR 3500 -5580 ms, TE 100 -140 ms, and NEX 2, for T2 weighting; and TR 11,000 ms, TE 140 ms, TI 2800 ms, and NEX 2, for FLAIR. Gadolinium chelate was not administered. DWI was obtained with a single-shot echo-planar imaging technique (b-value, 0 and 1000 seconds/mm 2 ) on either axial or coronal planes with automatic generation of ADC maps. Raw data were available for retrospective ADC value calculation in 4 examination

Pathophysiological role of inflammatory molecules in paediatric ischaemic brain injury.

Ischaemic stroke is one of the major causes of death and lifelong disability also in the paediatric population. Strong scientific effort has been put to clarify the pathophysiology of this disease in adults. However, only few studies have been performed in children. Preliminary results indicate that pathophysiological processes might differently affect the poststroke neuronal injury in neonates as compared to children. During the neural development, selective molecular mechanisms might be differently triggered by an ischaemic insult, thus potentially resulting in defined postischaemic clinical outcomes. Basic research studies in neonatal animal models of cerebral ischaemia have recently shown a potential role of soluble inflammatory molecules (such as cytokines, chemokines and oxidants) as pivotal players of neuronal injury in both perinatal and childhood ischaemic stroke. Although larger clinical trials are still needed to confirm these preliminary results, the potential benefits of selective treatments targeting inflammation in perinatal asphyxia encephalopathy might represent a promising investigation field in the near future. In this review, we will update evidence on the pathophysiological role of soluble inflammatory mediators in neonatal and childhood ischaemic stroke. Recent evidence on potential anti-inflammatory treatments to improve paediatric stroke prognosis will be discussed

CC and CXC chemokines are pivotal mediators of cerebral injury in ischaemic stroke.

The definition of ischaemic stroke has been recently updated as an acute episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischaemia in the presence of a cerebral infarction. This "tissular" definition has highlighted the importance of pathophysiological processes underlying cerebral damage. In particular, post- ischaemic inflammation in the brain and in the blood stream could influence crucial steps of the tissue injury/repair cascade. CC and CXC chemokines orchestrate the inflammatory response in atherosclerotic plaque vulnerability and cerebral infarction. These molecules exert their activities through the binding to selective transmembrane receptors. CC and CXC chemokines modulate crucial processes (such as inflammatory cell recruitment and activation, neuronal survival, neoangiogenesis). On the other hand, CXC chemokines could also modulate stem cell homing, thus favouring tissue repair. Given this evidence, both CC and CXC chemokines could represent promising therapeutic targets in primary and secondary prevention of ischaemic stroke. Only preliminary studies have been performed investigating treatments with selective chemokine agonists/antagonists. In this review, we will update evidence on the role and the potential therapeutic strategies targeting CC and CXC chemokines in the pathophysiology of ischaemic stroke

Inferior olivary nucleus involvement in pediatric neurodegenerative disorders: does it play a role in neuroimaging pattern-recognition approach?

The diagnostic work up of neurometabolic/degenerative disorders is complex. In such context, identification of neuroradiological features suggestive of specific diagnoses is useful to prompt further diagnostic tests. Involvement of the inferior olivary nucleus (ION) has been reported in several pathologic conditions, either as a primary manifestation of disease or secondary to hypertrophic olivary degeneration (HOD). In this study, we analyzed a cohort of 95 children with different neurometabolic/degenerative diseases involving the brainstem and cerebellum, with the aim to evaluate whether ION involvement plays a role in a neuroimaging-based pattern-recognition approach. A total of 13 patients (13.7%) showed bilateral high-signal intensity and enlargement of the ION on T2-weighted images, while 16 (16.8%) had ION T2-hyperintensity without olivary nucleus enlargement. Our study demonstrates that ION involvement is not rare in children with neurometabolic/degenerative disorders. Two main neuroradiological patterns, that is, "T2-hyperintense signal" and "T2-hyperintense signal with enlargement" are found. These patterns can be related to different etiologies, and do not suggest specific diagnoses. Primary ION lesion can be characterized by olivary swelling, and the differentiation from typical secondary HOD may be difficult

Anti-Glutamic Acid Decarboxylase Limbic Encephalitis Without Epilepsy Evolving Into Dementia With Cerebellar Ataxia

OBJECTIVES: To expand the spectrum of the clinical presentation of anti-glutamic acid decarboxylase antibodies-related limbic encephalitis and to improve the recognition of this entity. DESIGN: Case study. SETTING: University hospital. Patient An 11-year-old-girl with progressive mood and behavioral disorder, speech impairment, and short-term memory impairment who manifested cerebellar ataxia with nystagmus during the disease course. INTERVENTIONS: Blood and cerebrospinal fluid analysis including autoantibodies, electroencephalography, brain and spinal magnetic resonance imaging, and cognitive and neuropsychological assessment were performed. High-dose methylprednisolone sodium succinate pulses, cycles of intravenous immunoglobulins, mycophenolate mofetil, and rituximab as well as antipsychotics and benzodiazepine were administered. RESULTS: Diagnosis of anti-glutamic acid decarboxylase antibodies-related limbic encephalitis was made. The clinical features during the first months of disease included only mood, behavioral, and memory impairment. After 5 months, despite immunotherapies, cerebellar ataxia with nystagmus appeared with brain magnetic resonance imaging evidence of cerebral atrophy. No clinical or infraclinical seizures were recorded during follow-up. CONCLUSIONS: Anti-glutamic acid decarboxylase antibodies-related limbic encephalitis can present with only behavioral or neuropsychological symptoms without any epileptic disorder. Moreover, cerebellar ataxia related to anti-glutamic acid decarboxylase antibodies can be observed in patients with limbic encephalitis during the disease course

Anti-NMDAR encephalitis misdiagnosed as Hashimoto's encephalopathy.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a well-defined autoimmune disorder. Hashimoto's encephalopathy (HE) is a still controversial entity, lacking definite diagnostic criteria. We described a 14-year-old-girl presenting with a clinical picture consistent with the diagnosis of anti-NMDAR encephalitis, confirmed by NMDAR antibody testing. Four years earlier, she had presented a similar episode of acute encephalopathy diagnosed as HE. Anti-NMDAR encephalitis and HE share similar clinical features so that the differential diagnosis can be difficult if specific antibodies are not tested. The correct diagnosis of anti-NMDAR encephalitis is crucial to plan the appropriate management and follow-up, namely in term of oncological screening, since it can be paraneoplastic in origin. We suggest to re-evaluate the clinical history of all subjects with previous HE diagnosis in order to evaluate the possible diagnosis of anti-NMDAR encephalitis and plan the appropriate management of these patients