Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability.

J Clin Invest. 2020 03 02;130(3):1431-1445

Authors: Li L, Ghorbani M, Weisz-Hubshman M, Rousseau J, Thiffault I, Schnur RE, Breen C, Oegema R, Weiss MM, Waisfisz Q, Welner S, Kingston H, Hills JA, Boon EM, Basel-Salmon L, Konen O, Goldberg-Stern H, Bazak L, Tzur S, Jin J, Bi X, Bruccoleri M, McWalter K, Cho MT, Scarano M, Schaefer GB, Brooks SS, Hughes SS, van Gassen KLI, van Hagen JM, Pandita TK, Agrawal PB, Campeau PM, Yang XJ

Abstract
Epigenetic integrity is critical for many eukaryotic cellular processes. An important question is how different epigenetic regulators control development and influence disease. Lysine acetyltransferase 8 (KAT8) is critical for acetylation of histone H4 at lysine 16 (H4K16), an evolutionarily conserved epigenetic mark. It is unclear what roles KAT8 plays in cerebral development and human disease. Here, we report that cerebrum-specific knockout mice displayed cerebral hypoplasia in the neocortex and hippocampus, along with improper neural stem and progenitor cell (NSPC) development. Mutant cerebrocortical neuroepithelia exhibited faulty proliferation, aberrant neurogenesis, massive apoptosis, and scant H4K16 propionylation. Mutant NSPCs formed poor neurospheres, and pharmacological KAT8 inhibition abolished neurosphere formation. Moreover, we describe KAT8 variants in 9 patients with intellectual disability, seizures, autism, dysmorphisms, and other anomalies. The variants altered chromobarrel and catalytic domains of KAT8, thereby impairing nucleosomal H4K16 acetylation. Valproate was effective for treating epilepsy in at least 2 of the individuals. This study uncovers a critical role of KAT8 in cerebral and NSPC development, identifies 9 individuals with KAT8 variants, and links deficient H4K16 acylation directly to intellectual disability, epilepsy, and other developmental anomalies.

PMID: 31794431 [PubMed - indexed for MEDLINE]

Hemophagocytic Lymphohistiocytosis: A Rare Complication of an Ultrarare Lysosomal Storage Disease.

J Pediatr Hematol Oncol. 2020 05;42(4):310-312

Authors: Chabchoub I, Boudabbous H, Maaloul I, Ben Abdelaziz R, Ben Chehida A, Ayadi L, Kamoun T, Tebib N, Boudaouara T, Bekri S, Hachicha M

Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening hyperinflammatory condition that may be triggered by infections, autoimmune and immunologic disorders, malignancies, and metabolic diseases. Early and accurate diagnosis of HLH and its underlying cause is of paramount importance for proper management and prognosis. We report the case of a Tunisian 21-month-old girl who initially presented clinical features of HLH related to a lysosomal acid lipase deficiency. The genetic sequence analysis of the LIPA gene revealed a never described homozygous mutation c.966G>C (p.Gln322His). The parents were heterozygous for this mutation. Enzyme replacement therapy was not provided for the patient. She received etoposide, corticosteroids, and cyclosporine for the HLH. She is waiting for hematopoietic stem cell transplantation. To the best of our knowledge, this is the second Tunisian case of secondary HLH complicating lysosomal acid lipase deficiency related to a new homozygous mutation: c.966G>C (p.Gln322His).

PMID: 31318819 [PubMed - indexed for MEDLINE]

Histiocytic Sarcoma.

Isr Med Assoc J. 2020 10;22(10):579-581

Authors: Tocut M, Vaknine H, Potachenko P, Elias S, Zandman-Goddard G

Abstract
BACKGROUND: Histiocytic sarcoma (HS) is a rare hematopoietic malignancy originating from the monocyte/macrophage bone marrow lineage. HS can occur in isolation or in association with other hematological neoplasms such as non-Hodgkin lymphoma (NHL), myelodysplasia, or acute leukemia. Clinically, HS can affect lymph nodes, gastrointestinal tract, skin, bone marrow, and spleen as well as the central nervous system. Most cases of HS follow an aggressive clinical course, with most patients dying of progressive disease within one year of diagnosis.

PMID: 33070490 [PubMed - indexed for MEDLINE]

Case series: an essential study design to build knowledge and pose hypotheses for rare and new diseases.

J Bras Pneumol. 2020 Sep 07;46(4):e20200389

Authors: Torres-Duque CA, Patino CM, Ferreira JC

PMID: 32901691 [PubMed - indexed for MEDLINE]

Acute cerebellar ataxia: a rare Toscana Virus (TOSV) meningoencephalitis complication.

Int J Neurosci. 2020 Mar;130(3):276-278

Authors: Suardi LR, Di Lauria N, Pozzi M, Rogasi PG, Barilaro A, Azzolini F, Prestipino E, Colao MG, Rossolini GM, Bartoloni A

Abstract
Purpose: Arbovirosis, viral infection transmitted by arthropods, is a widespread health problem. In Italy, as well for all Mediterranean basin, from late spring to the end of summer, Toscana Virus (TOSV), a sandfly borne virus, accounts for the majority of aseptic meningitis/meningoencephalitis cases. TOSV meningitis/meningoencephalitis has usually a self-extinguishing benign course. Our aim is to report a case of a young healthy women diagnosed with Toscana Virus meningoencephalitis with a complicated clinical course.Materials and methods/results: Case report of a 33-years old woman, admitted to the Infectious Diseases Unit at Careggi General Hospital (Florence-Italy), with a diagnosis of Toscana Virus meningoencephalitis. Seventy-two hours after the admission, she developed typical symptoms, as impaired legs coordination, slurred speech, stumbling and dysmetria, of acute cerebellar ataxia (ACA). Urgent neurological assessment was provided performing an electroencephalography study followed by a brain and brainstem magnetic resonance imaging. In the meanwhile, bilateral nystagmus arised. Through neurologist consultation ACA clinical diagnosis was then made and intravenous steroid therapy was administered with prompt symptoms resolution. The patient was finally discharged at day 10 since the ACA onset in good clinical conditions.Conclusions: To raise awareness among physicians about possible neurological complications during Toscana Virus meningoencephalitis.

PMID: 31554442 [PubMed - indexed for MEDLINE]

The P72R Polymorphism in R248Q/W p53 Mutants Modifies the Mutant Effect on Epithelial to Mesenchymal Transition Phenotype and Cell Invasion via CXCL1 Expression.

Int J Mol Sci. 2020 Oct 28;21(21):

Authors: De Souza C, Madden JA, Minn D, Kumar VE, Montoya DJ, Nambiar R, Zhu Z, Xiao WW, Tahmassebi N, Kathi H, Nelson N, Karnezis AN, Chien J

Abstract
High-grade serous carcinoma (HGSC), the most lethal subtype of epithelial ovarian cancer (EOC), is characterized by widespread TP53 mutations (>90%), most of which are missense mutations (>70%). The objective of this study was to investigate differential transcriptional targets affected by a common germline P72R SNP (rs1042522) in two p53 hotspot mutants, R248Q and R248W, and identify the mechanism through which the P72R SNP affects the neomorphic properties of these mutants. Using isogenic cell line models, transcriptomic analysis, xenografts, and patient data, we found that the P72R SNP modifies the effect of p53 hotspot mutants on cellular morphology and invasion properties. Most importantly, RNA sequencing studies identified CXCL1 a critical factor that is differentially affected by P72R SNP in R248Q and R248W mutants and is responsible for differences in cellular morphology and functional properties observed in these p53 mutants. We show that the mutants with the P72 SNP promote a reversion of the EMT phenotype to epithelial characteristics, whereas its R72 counterpart promotes a mesenchymal transition via the chemokine CXCL1. These studies reveal a new role of the P72R SNP in modulating the neomorphic properties of p53 mutants via CXCL1, which has significant implications for tumor invasion and metastasis.

PMID: 33126568 [PubMed - as supplied by publisher]

Amassing Granular Information About Eosinophilic Gastrointestinal Disorders Through Multicenter Cooperation: A Paradigm for Rare Disease Study.

Dig Dis Sci. 2020 07;65(7):1880-1881

Authors: Ravi A, Katzka DA

PMID: 31970606 [PubMed - indexed for MEDLINE]

A pragmatic, adaptive clinical trial design for a rare disease: The FOcal Cerebral Arteriopathy Steroid (FOCAS) trial.

Contemp Clin Trials. 2019 11;86:105852

Authors: Park Y, Fullerton HJ, Elm JJ

Abstract
BACKGROUND: Pediatric stroke investigators identified as their top research priority a clinical trial of corticosteroids for focal cerebral arteriopathy (FCA). However, FCA is both rare and an acute condition making it infeasible to enroll the large sample sizes needed for standard, confirmatory clinical trials. We present a pragmatic approach to clinical trial design that may inform the approach to other rare disorders.
METHODS: We surveyed pediatric stroke experts to determine the level of evidence that would impact their clinical management of FCA. Incorporating survey results, a randomized, group sequential Bayesian adaptive design was proposed based on a quantitative radiologic outcome measure (change from baseline in change in the FCA Severity Score). Using accumulating information, the design determines whether intervention is better than control with high probability.
RESULTS: Among 21 (100%) respondents, the probability of corticosteroid efficacy that would lead the experts to treat was 30% (median). The probability of efficacy that would make them unwilling to randomize (because they would feel all children should receive corticosteroids) was 70%. Simulation studies with the proposed design showed that a total of 42 subjects controls the type I error rate at the desired level 0.20 and yields a smaller average sample size and trial duration compared to a conventional design.
CONCLUSIONS: Designs in rare diseases require special considerations; this is especially true for this childhood disease, which is both uncommon and acute. This design has incorporated expert consensus to establish the criteria for success, formal monitoring rules for safety, and early stopping rules.

PMID: 31614215 [PubMed - indexed for MEDLINE]

Effective treatment of disseminated superficial actinic porokeratosis with chemical peels - customary treatment for a rare disease.

J Dermatolog Treat. 2020 Nov;31(7):744-748

Authors: Lang BM, Peveling-Oberhag A, Zimmer S, Wegner J, Sohn A, Grabbe S, Staubach P

Abstract
Background: Disseminated superficial actinic porokeratosis (DSAP) is a rare dermatologic disorder of the epidermis. Often misdiagnosed as chronic UV-damage or actinic keratoses, patients are treated for years with different therapeutic options with little success. Current treatment options include imiquimod, ingenol mebutate, cryosurgery, photodynamic therapy and topical or systemic therapy with retinoids. Since those approaches show only little success or come along with major side effects, therapeutic alternatives are strongly requested. Methods: We report a series of five female patients with history of DSAP that were successfully treated with chemical peels. Results: All patients suffered from the disease for 14.4 years on average and all were refractory to at least two therapeutic options, mostly imiquimod and topical tretinoin. Patients were treated with glycolic acid 50% and salicylic acid 25% in a two-layer-technique. After a mean of three cycles every 6 weeks a clear reduction in lesion was assessed by physicians. Patients were highly satisfied with outcome and rare occurrence of side effects as assessed by TSQM questionnaire. Conclusion: Chemical peels are safe and well tolerated treatment options for patients with refractory porokeratosis. As characteristic for chronic diseases, frequent repetition of treatment is needed in order to control disease activity.

PMID: 31018713 [PubMed - indexed for MEDLINE]

8 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2020/10/30

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Solitary neurofibroma of maxilla: a rare clinical entity.

BMJ Case Rep. 2020 Feb 28;13(2):

Authors: Grewal M, Saini N, Gautam S, Garg P

Abstract
Neurofibroma (NF) is a benign tumour of the peripheral nervous system which is rare in head and neck region. Head and neck NF are mostly located in the soft tissue and rarely seen intraosseously. These may present either as solitary lesions or as part of the generalised syndrome of neurofibromatosis or von Recklinghausen's disease of the skin. The intraosseous ones are most commonly seen as solitary lesions, rather than part of neurofibromatosis. The following report describes a unique case of a solitary neurofibroma of the maxilla without generalised syndrome of neurofibromatosis in a male patient.

PMID: 32111709 [PubMed - indexed for MEDLINE]

Cystic fibrosis: a rare disease emerging in China.

Sci China Life Sci. 2020 Jul;63(7):1082-1084

Authors: Zhang T, Tian X, Xu KF

PMID: 32103413 [PubMed - indexed for MEDLINE]

A Rare Case of a Left-sided Gallbladder Accompanied with an Aplastic Cystic Duct in a Patient with Acute Cholecystitis.

Am J Case Rep. 2020 Feb 19;21:e920821

Authors: Chatzifotiou D, Schnell M, Lupascu B, Gundlach M

Abstract
BACKGROUND A left-sided gallbladder without situs inversus is a rare congenital anomaly of the gallbladder with a prevalence ranging from 0.04-0.3%. CASE REPORT We present a case of a female patient, referred to our clinic with clinical features of an acute cholecystitis. After performing the standard preoperative investigations, which confirmed the diagnosis, the patient underwent a laparoscopic cholecystectomy. We found a left-sided gallbladder, attached to the lower surface of the left lobe of the liver. During the dissection in the Callot triangle an aplastic cystic duct was also identified. The extirpation of the gallbladder was performed anterograde, allowing a better exposition of the critical structures. CONCLUSIONS A left sided gallbladder is almost an incidental finding, which can be accompanied with further anomalies of the biliary tree. A combination of these 2 variations is very rare without any other reported cases in the literature.

PMID: 32071285 [PubMed - indexed for MEDLINE]

Percutaneous Pulsed Radiofrequency Treatment in a Patient with Chronic Bilateral Painful Glossopharyngeal Neuropathy.

Am J Case Rep. 2020 Feb 11;21:e920579

Authors: van Tilburg CWJ

Abstract
BACKGROUND Due to its rareness, we present a case of chronic, bilateral, painful glossopharyngeal neuropathy, which developed after nasal septum and inferior concha surgery, and was non-surgically treated with percutaneous pulsed radiofrequency at the glossopharyngeal nerve, using an extra-oral approach. CASE REPORT A 41-year-old Caucasian female patient (60 kg, 1.57 m, body mass index 24.8 kg/m²) was referred to the Pain Center by her general practitioner because of ongoing pressing pain in her throat 4 months after nasal septum and inferior concha surgery. Based upon medical history, physical examination and the results of additional questionnaires, a probable diagnosis of atypical neck pain was made, based on ongoing glossopharyngeal stimulation, involvement of the pterygopalatine ganglion or/and superior cervical ganglion, with secondary involvement of the muscles of the neck. We changed the analgesic regimen and performed a pulsed radiofrequency treatment of the glossopharyngeal nerve on both sides. The patient had made progress and reported that she actually felt better but she asked for repeat treatment because of residual complaints. We performed the procedure for a second time on both sides. The results of the questionnaires before (T0) treatment, 3 months after the first (T1) and 3 months after the second (T2) treatment are provided. After the second procedure, the patient reported that her swallowing complaints had further diminished, as well as the pain behind her ears. She stopped using pregabalin. Residual complaints were manageable. CONCLUSIONS In patients with painful glossopharyngeal neuropathy, a non-surgically treatment with percutaneous pulsed radiofrequency at the glossopharyngeal nerve, using an extra-oral approach, seems to be an effective and safe method to use.

PMID: 32041932 [PubMed - indexed for MEDLINE]

Symptomatic congenital Morgagni hernia presenting as a chest pain: a case report.

J Med Case Rep. 2020 Jan 18;14(1):13

Authors: Mohamed M, Al-Hillan A, Shah J, Zurkovsky E, Asif A, Hossain M

Abstract
BACKGROUND: Morgagni hernia is a rare form of congenital diaphragmatic hernia with a prevalence of 2-3%. It occurs due to a defect on the anterior part of the diaphragm, which allows abdominal organs to penetrate into the thoracic cavity. This condition can be detected during fetal life by routine ultrasonography or late during adult life. Late diagnosis of this condition in adults is extremely rare. According to our literature search, only a few cases of symptomatic hernia in adults have been reported so far. Surgery provides definitive treatment for patients with Morgagni hernia; it is always recommended for symptomatic and asymptomatic adult patients to avoid future complications such as volvulus, small bowel obstruction, incarceration, or strangulation. We report a case of a patient who presented with chest pain due to newly diagnosed congenital diaphragmatic hernia.
CASE PRESENTATION: A 29-year-old unemployed white man with no significant past medical history or family history of coronary artery disease, who was a current smoker with a 1-pack-per-day history, presented to our hospital with a 1-month history of intermittent chest pain. His chest pain was localized to the right side with a pressure-like quality, moderate intensity 4-6/10, nonradiating, and relieved by standing up and worsened by lying flat. His pain was not associated with increase or decrease in activity level. The pain had progressively worsened, which prompted the patient to come to the emergency room. The patient was admitted for further evaluation. A chest x-ray showed a suspected loop of bowel on the right side of the chest. Subsequently, the patient underwent computed tomography of the chest, which revealed a 7-cm defect in the right hemidiaphragm with a large amount of intra-abdominal fat and a loop of the proximal transverse colon within the hernial sac. The patient was evaluated by a surgeon and eventually underwent laparoscopic repair of the diaphragmatic hernia with mesh repair. In follow-up, the patient's symptoms resolved.
CONCLUSION: Morgagni hernia is a rare form of congenital diaphragmatic hernia. It is commonly found either in the first few hours of life or in the antenatal period. It is less common in adults and is usually diagnosed accidentally in asymptomatic patients. Symptomatic adult cases are extremely rare. Respiratory symptoms are the most common presenting symptoms. The primary management for both symptomatic and incidentally discovered asymptomatic cases of Morgagni hernia is surgical correction. Various thoracic and abdominal surgical approaches have been described without a clear consensus on preference for operative repair technique.

PMID: 31952551 [PubMed - indexed for MEDLINE]

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2020/10/28

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2020/10/28

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Vitreous metabolomics profiling of proliferative diabetic retinopathy.

Diabetologia. 2020 Oct 25;:

Authors: Tomita Y, Cagnone G, Fu Z, Cakir B, Kotoda Y, Asakage M, Wakabayashi Y, Hellström A, Joyal JS, Talukdar S, Smith LEH, Usui Y

Abstract
AIMS/HYPOTHESIS: Proliferative diabetic retinopathy (PDR) with retinal neovascularisation (NV) is a leading cause of vision loss. This study identified a set of metabolites that were altered in the vitreous humour of PDR patients compared with non-diabetic control participants. We corroborated changes in vitreous metabolites identified in prior studies and identified novel dysregulated metabolites that may lead to treatment strategies for PDR.
METHODS: We analysed metabolites in vitreous samples from 43 PDR patients and 21 non-diabetic epiretinal membrane control patients from Japan (age 27-80 years) via ultra-high-performance liquid chromatography-mass spectrometry. We then investigated the association of a novel metabolite (creatine) with retinal NV in mouse oxygen-induced retinopathy (OIR). Creatine or vehicle was administered from postnatal day (P)12 to P16 (during induced NV) via oral gavage. P17 retinas were quantified for NV and vaso-obliteration.
RESULTS: We identified 158 metabolites in vitreous samples that were altered in PDR patients vs control participants. We corroborated increases in pyruvate, lactate, proline and allantoin in PDR, which were identified in prior studies. We also found changes in metabolites not previously identified, including creatine. In human vitreous humour, creatine levels were decreased in PDR patients compared with epiretinal membrane control participants (false-discovery rate <0.001). We validated that lower creatine levels were associated with vascular proliferation in mouse retina in the OIR model (p = 0.027) using retinal metabolomics. Oral creatine supplementation reduced NV compared with vehicle (P12 to P16) in OIR (p = 0.0024).
CONCLUSIONS/INTERPRETATION: These results suggest that metabolites from vitreous humour may reflect changes in metabolism that can be used to find pathways influencing retinopathy. Creatine supplementation could be useful to suppress NV in PDR. Graphical abstract.

PMID: 33099660 [PubMed - as supplied by publisher]

Pre-operative ultrasound diagnosis and successful surgery of a stomach incarcerated in epigastric hernia: a rare case report.

Folia Med Cracov. 2020;60(1):55-60

Authors: Gryglewski A, Wantuch K, Wójciak S, Opach Z, Richter P

Abstract
An incarcerated epigastric hernia (localized in linea alba) is a very rare observation. Here, we present a case of a 66-year-old white male who was admitted to the emergency department due to vomiting and epigastric pain. On physical examination, the only observed abnormality was a painless soft epigastric tumor located in the upper midline, measuring about 12 cm in diameter. The patient claimed that he had the tumor for more than 30 years and it never changed in diameter nor caused him any discomfort. A lipoma was initially suspected. However, an ultrasound of the abdomen revealed an incarcerated stomach, trapped due to the defect in the epigastric abdominal wall. The patient was sent for surgery and the presence of an incarcerated epigastric hernia of the linea alba, which contained the anterior wall of the stomach was confirmed. The presented case confirms that the use of ultrasonography may be an effective method to recognize unusual types of hernias, and that ultrasonography should be routinely used in emergency departments.

PMID: 32658212 [PubMed - indexed for MEDLINE]

Pustular Psoriasis: The Dawn of a New Era.

Acta Derm Venereol. 2020 Jan 30;100(3):adv00034

Authors: Bachelez H

Abstract
Pustular psoriasis is a clinically heterogeneous entity of different, orphan disease subtypes, among which the most clearly defined are generalized pustular psoriasis, palmoplantar psoriasis, and acrodermatitis continua of Hallopeau. Although phenotypically and genetically distinct from psoriasis vulgaris, these subtypes may be associated with plaque psoriasis lesions, establishing the rationale for their inclusion in the psoriasis spectrum. Unlike psoriasis, however, their genetic background is thought to be mainly monogenic, as shown by the recent identification of mutations in 3 different genes of the skin innate immune system; IL36RN, CARD14 and AP1S3. These major advances in the understanding of the disease pathogenesis have led to the design and ongoing development of tailored therapeutic approaches, which are highly necessary given the refractory nature of pustular psoriasis in response to most available antipsoriatic drugs.

PMID: 31971600 [PubMed - indexed for MEDLINE]