Mona Al Mukaddam1, Kin Cheung2, Sammi Kile3, Michelle Davis3, Frederick S. Kaplan1,4 Robert J. Pignolo5*

1Departments of Medicine, Orthopaedic Surgery, and The Center for Research in FOP and Related Disorders, The Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA, USA

2BioSAS Consulting, Inc., Wellesley, Massachusetts, USA

3International FOP Association (IFOPA), North Kansas City, Missouri, USA

4Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine

5Chair, Geriatric Medicine & Gerontology, Robert and Arlene Kogod Professor of Geriatric Medicine, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN, USA

Background:Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disease characterized by malformed great toes and progressive heterotopic ossification (HO) in soft tissues. Current standard-of-care is aimed at palliation of symptoms; there are no currently approved therapies to prevent HO. Recurrent episodes of HO starting in early life lead to cumulative disability, severe functional limitations, and shortened life span. Most individuals require assistive devices and extensive caregiver support before the second decade of life. Caregiver support is thought to be high, but the timing and extent of caregiver support in FOP has not been formally assessed. Methods: Using data from the International FOP Association (IFOPA) Global Registry on 299 patients (median age 21 years; range 0.1 to 78 years) from 54 countries, we characterized the extent of caregiver support by assessing the number of part-time and full-time caregivers and school aides reported by participants, based on age. Results: Over 50% of FOP Registry respondents reported a need for part-time or full-time home personal care attendants. The percentage of individuals who reported a requirement for bathing attendants and part- or full-time home personal care attendants increased with age (>1 part-time or full-time caregiver exceeded 30% for individuals >15 years of age), as did the number of part-time or full-time attendants. Support from school aides peaked between 9 and 15 years of age. Conclusion: Caregiver support in FOP is high in terms of time and amount of support needed, increases rapidly with age, and is substantial by the second decade of life. These findings highlight the urgent need for transformative treatments that will preserve the independence of individuals with FOP.

DOI: 10.29245/2572-9411/2021/1.1200 View / Download Pdf

Maria Goretti Polito1, Michelle Tiveron Passos1, Danilo Euclides Fernandes1, Gianna Mastroianni-Kirsztajn2*

1Department of Medicine (Nephrology), Federal University of São Paulo, São Paulo-SP, Brazil

2Associate Professor of Medicine, Department of Medicine (Nephrology), Federal University of São Paulo, São Paulo-SP, Brazil

Background: Focal segmental glomerulosclerosis (FSGS) is an important cause of end-stage kidney disease in children and adults. Although most cases are sporadic (s), familial (f) presentation is also described. The purpose of the present study was to establish clinical and laboratory profiles of fFSGS vs. primary sFSGS, contributing to the distinguishing diagnosis in clinical practice and best management, in particular when mutation analysis is not available.
Methods: Demographic, clinical and laboratorial parameters were studied in 124 patients 12 years and older with FSGS, subdivided in sFSGS (n=89) and fFSGS (n=35).
Results: General and clinical features were similar, as well as serum creatinine at disease presentation. Proteinuria levels were more frequently ≥ 3g/day in sFSGS (63.8%) than in fFSGS (44%, p=0.080), and serum albumin levels were < 3.0 g/dL in 45.8% and 20%, respectively (p=0.046). The groups were statistically different regarding steroid resistance, corresponding to 60% in sFSGS and 100% in fFSGS (p=0.001).
Conclusions: The studied groups were clinically similar, except that proteinuria tended to be higher (nephrotic range) and serum albumin was lower in sFSGS vs. fFSGS. In addition, all treated fFSGS patients were steroid resistant. At presentation it is important to characterize if the patient has fFSGS, that will contribute to further disease management, and disease history will be the first clue for such differential diagnosis.

DOI: 10.29245/2572-9411/2021/1.1199 View / Download Pdf

Ichraf Kraoua1,2,3, Thouraya Ben Younes1,2,3*, Virginie Garcia4, Hanene Benrhouma1,2,3, Hedia Klaa1,2,3, Aida Rouissi1,2,3, Thierry Levade4,5, Ilhem Ben Youssef-Turki1,2,3

1Department of Child and Adolescent Neurology. National Institute Mongi Ben Hmida of Neurology. Tunis, Tunisia

2Research Laboratory LR18 SP04. National Institute Mongi Ben Hmida of Neurology. Tunis, Tunisia

3University of Tunis El Manar, Faculty of Medicine of Tunis. Tunis, Tunisia

4Cancer Research Center of Toulouse, INSERM UMR1037 and Université Paul Sabatier, Toulouse, France

5Laboratory of Metabolic Biochemistry, Federative Institute of Biology, CHU Purpan, Toulouse, France

Farber Disease is an autosomal recessive inherited lysosomal storage disorder which is characterized by tissue accumulation of ceramide. It is caused by mutations within ASAH1 encoding for acid ceramidase. It represents a rare condition. Only twenty seven cases have been reported. Seven subtypes of Farber disease have been identified. The clinical presentation is characterized by the appearance of subcutaneous skin nodules, bone and joint deformities, and progressive hoarseness. Neurological symptoms as psychomotor delay or regression, hypotonia, seizures, and peripheral neuropathy were reported in some subtypes of Farber disease. The nervous system involvement is correlated to poor prognosis. In this study, we report on clinical, biochemical and molecular findings of two Tunisian siblings with Farber disease.

DOI: 10.29245/2572-9411/2020/2.1197 View / Download Pdf

Moira Liljesthröm1, Robert J. Pignolo2, Frederick S. Kaplan3*

1President of Fundación FOP, Argentina; Argentine Representative to the International President’s Council of the International Fibrodysplasia Ossificans Progressiva Association (IFOPA), Buenos Aires, Argentina

2Department of Medicine, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, USA

3The Departments of Orthopaedic Surgery, Medicine and The Center for Research in FOP & Related Disorders, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA 19104, USA

Background: Fibrodysplasia Ossificans Progressiva (FOP) is an ultrarare disease, but the geographic distribution and regional prevalence of the condition are unknown. This study was undertaken to determine the emerging global population of FOP patients who were associated with a regional, national or international FOP organization.

Results: This study interrogated the patient registration database of the International Fibrodysplasia Ossificans Progressiva Association (IFOPA) and those of the 16 regional or national FOP organizations in order to assemble a non-redundant worldwide census of patients living with FOP in 2016 who were associated with a pre-identified FOP community. The total registered population of the global FOP community was 834 individuals [445 females (54%), 387 males (46%), 2 unassigned] distributed in 67 countries and six continents. The apparent prevalence of registered and confirmed FOP patients varied substantially from approximately 0.65 per million in North America, 0.47 per million in Western Europe, and 0.27 per million in Latin America, to 0.05 per million in Africa and nearly 0.04 per million in the Asia-Pacific region.

Conclusions: The high variability in apparent prevalence is likely associated with lack of awareness of FOP in under-represented medical communities, delay in achieving the correct FOP diagnosis, lack of supporting regional infrastructure and inability of individuals with FOP to reach a local FOP organization or the international FOP community. Emerging knowledge of the apparent prevalence of FOP can serve as a catalyst for resource allotment; physician, patient and community education and outreach; clinical trial recruitment and global networking to achieve a more globally robust and interconnected FOP community.

DOI: 10.29245/2572-9411/2020/2.1196 View / Download Pdf

Neil A. Judd*, Hannah S. Calhoun, Virginia Chu, Stacey Reynolds

Virginia Commonwealth University

Barth syndrome (BTHS) is a rare genetic disorder commonly characterized by cardiomyopathy, muscle weakness, abnormal fatigability, and exercise intolerance. Sleep problems have been identified informally within the BTHS community though it has never been systematically studied. This study aimed to (1) objectively quantify sleep in males with BTHS, (2) examine the relationship between sleep and physical activity levels, and (3) examine age-related trends in data. Twenty participants (7 adults and 13 children) with BTHS completed the study. Each participant wore an Actigraph GT9X activity tracker and completed a sleep diary for 14 consecutive days. Energy expenditure was calculated at various time periods: early morning, late morning, early afternoon, late afternoon, early evening, and late evening. Generalized Linear Models support statistically significant interactions between physical activity levels throughout the day and sleep parameters (sleep latency, efficiency, and nighttime awakenings). Trend analysis showed children had a longer sleep latency, higher sleep efficiency, and more nighttime awakenings than adults and were more active overall. Some of the findings in our study contradict current literature pointing to a relationship between sleep and physical activity levels in the typical population. This suggests other factors may impact decreased sleep in BTHS and warrants future studies into the causes of decreased sleep and the relationship to physical activity in this population.

DOI: 10.29245/2572-9411/2020/2.1194 View / Download Pdf

Rodrigo F.C. Azambuja Neves1,2, Patrícia Varela3, Danilo Euclides Fernandes1*, Michelle T. P. Riguetti1, Simone Geraldini1, Gustavo Ferreira da Mata1, Carmen Mendes4, Ana Maria Martins4, João Bosco Pesquero3, Gianna Mastroianni Kirsztajn1*

1Section of Glomerulopathies, Nephrology Division, Federal University of São Paulo, São Paulo, Brazil

2Radiology Service of Hospital do Rim, São Paulo, Brazil

3Department of Biophysics, Federal University of São Paulo, São Paulo, Brazil

4IGEIM (Innate Errors of Metabolism), Federal University of São Paulo, São Paulo, Brazil

Introduction: Renal impairment in Fabry disease is widely known, but the occurrence of renal cysts as a manifestation of the disease should still be highlighted among radiologists and other physicians.

Objectives: To compare the presence of parapelvic cysts between Fabry disease and other causes of chronic kidney disease (CKD).

Methods: We evaluated demographic, clinical and laboratory data, as well as kidney ultrasound (US) findings in 91 patients with Fabry disease (n=37) and different glomerulopathies (n=54).

Results: Both groups were similar in age (p = 0.29), gender (p = 0.98), eGFR (p = 0.10) and CKD stages (p = 0.19).Presence of parapelvic cysts differed significantly between those two groups (p < 0.0001 in right and left kidneys; Cohen’s h = 1.15). When present, diameters of the parapelvic cysts were similar. Both groups had signs of CKD such as corticomedullary undifferentiation. None of the mutations we found in GLA gene was associated with a higher prevalence of parapelvic cysts.

Conclusions: When compared to different glomerulopathies, parapelvic cysts were more frequently found in Fabry disease despite age, gender and stage of CKD. Parapelvic cysts on ultrasound can raise suspicion on Fabry disease in patients with kidney disease of unknown etiology especially in the context of a familial nephropathy.

DOI: 10.29245/2572-9411/2020/2.1195 View / Download Pdf

Claudio Alves Andrade Cardoso#, Danilo Euclides Fernandes#*, Michelle Tiveron Passos Riguetti, Gianna Mastroianni Kirsztajn

Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo - SP, 04021-001, Brazil

INTRODUCTION: Hearing loss is a typical finding in Alport syndrome (sAlport) caused by a genetic defect in the type IV collagen synthesis. Depending on the criteria, these individuals may be diagnosed with normal hearing.

OBJECTIVE: To compare the prevalence of hearing loss according to different criteria – World Health Organization, WHO; Global Burden Disease, GBD and Clark – in patients with sAlport and segmental and focal glomeruloesclerosis (FSGS).

MATERIALS AND METHODS: This is a cross-sectional pilot study. Pure-tone audiometry was carried out in patients with sAlport and FSGS (glomerulopathy which was selected as a control group).

RESULTS: We assessed 13 patients (6 with sAlport and 7 with FSGS). Under the WHO criteria, no patient had hearing loss. The prevalence of hearing loss was similar according to GBD criteria (16.67% and 14.29% in the sAlport and FSGS groups, respectively). Clark's criteria, instead, revealed a higher prevalence of hearing loss in the sAlport group (66.67%) vs. FSGS (28.57%).

CONCLUSION: The prevalence of hearing loss in the sAlport group varied depending on the criteria (from nonexistent to 67%). We consider that a critical evaluation of the hearing thresholds may help physicians to early detect minimal hearing impairment even though the report says, “normal hearing”.

DOI: 10.29245/2572-9411/2020/2.1193 View / Download Pdf

An Nguyen1, Amr S. Soliman2*, Ahmed Hablas3, Mohamed Ramadan3, Ibrahim Seifeldin3

1Milken Institute School of Public Health, The George Washington University, Washington, DC, USA

2CUNY School of Medicine, New York, NY, USA

3Gharbiah Cancer Society, Tanta, Gharbiah, Egypt

BACKGROUND: Inflammatory Breast Cancer (IBC) is a rare but aggressive form of breast cancer, constituting about 1-5% of breast cancers in the U.S. but about 11% in Egypt. The etiology of IBC is unknown, but the distribution of residence of IBC and non-IBC patients may provide clues to the disease risk factors. Therefore, we investigated the geographic distribution of IBC and non-IBC in the province of Gharbiah, Egypt.

METHODS: All breast cancers diagnosed during the period of January 2009 to December 2010 were retrieved from the Gharbiah Population-based registry. IBC cases were obtained from a case-control study conducted in the same region and period. Incidence rates were calculated for IBC and non-IBC for each of the eight districts and their rural/urban regions.

RESULTS: The incidence of IBC was higher in rural than urban areas, in contrast to the incidence of non-IBC. Clustering of IBC and non-IBC was observed more in urban than in rural areas. IBC clusters were detected in 7 of the 8 urban areas of Gharbiah, with the highest incidence identified in urban Kafr El-Zayat. Non-IBC clusters were distributed in all 8 urban areas of Gharbiah without clustering, with highest incidence is identified in urban Tanta.

CONCLUSION: Our results showed different geospatial distributions of IBC and non-IBC relative to the regional environmental exposures. Future studies should explore specific environmental exposures that may contribute to the geographic distribution of IBC and non-IBC in the region to further explore the etiology of IBC and non-IBC.

DOI: 10.29245/2572-9411/2020/2.1192 View / Download Pdf

Zainab Almasseri1, Manal Nicolas- Jilwan2, Ahmad Khaled Almadani1, Mohammad Al-Owain1,5, Rousseau Gama3,4, Raashda Ainuddin Sulaiman1,5*

1Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

2Department of Radiology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

3Blood sciences, The Royal Wolverhampton NHS trust, Wolverhampton, UK

4School of Medicine and Clinical Practice, Wolverhampton University, UK

5College of Medicine, Alfaisal University, Riyadh, Saudi Arabia

6-Pyruvoyl-tetrahydropterin synthase (PTPS) deficiency results in depletion of the brain neuro-transmitters serotonin and dopamine. Since dopamine is the physiological inhibitor of pituitary prolactin secretion, hyperprolactinemia is common in patients with PTPS deficiency. Serum prolactin concentrations are used for the monitoring and optimization of L-Dopa therapy. We report three adult patients with PTPS deficiency who had persistent hyperprolactinemia unresponsive to high dose L-Dopa therapy, and pituitary imaging confirmed microadenoma. In the presence of prolactinoma, serum prolactin is an unreliable tool for treatment monitoring in these patients. This report emphasizes the need to exclude other causes of hyperprolactinemia including prolactinoma, in patients who are compliant with optimized L-Dopa treatment and their prolactin levels remain significantly high.

DOI: 10.29245/2572-9411/2020/2.1191 View / Download Pdf

Pushkar Kulkarni*, Aarti Sevilimedu*

Centre for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad, Telangana, 500046, India

Fragile X Syndrome (FXS) is a rare disease and the leading monogenic cause of Autism Spectrum Disorders (ASD). It is caused by the silencing of the Fragile X mental retardation (FMR1) gene and the subsequent reduction or loss of fragile X mental retardation protein (FMRP). The clinical effects seen in FXS patients are several and highly variable making it difficult to model them in a single model or even one organism. Furthermore, several human behaviours can be measured only through surrogate endpoints in animals. Therefore, it has been challenging to develop in vivo models of FXS for drug discovery.

This review endeavours to consolidate the information on all available in vivo models for FXS specifically with a focus on their suitability for drug development, with the objective of identifying gaps and potential solutions. To do so, we have summarised the major clinical characteristics and possible mechanisms underlying clinical phenotypes associated with FXS and other disorders that arise from abnormalities in the FMR1 locus, such as fragile-X associated tremor/ataxia syndrome (FXTAS), fragile-X-associated neuropsychiatric disorders (FXAND) including ASD and fragile x-associated primary ovarian insufficiency (FXPOI). We then connect clinical features to phenotypes observed in available in vivo FXS models where possible, covering a wide range of organisms from primates, rats, mice, zebrafish, fruit fly and zebra finches. For each model organism, we list the technology of model creation, phenotypes/assays, mechanistic basis of disease manifestation and specific advantages or disadvantages of the model in the context of drug discovery.

Finally, we have highlighted the missing pieces in FXS modelling and propose strategies to address them, considering aspects of modelling spectrum disorders, repeat expansion and silencing, new functions of FMRP and identification of efficacious treatments.

DOI: 10.29245/2572-9411/2020/1.1190 View / Download Pdf

Moustapha Niasse1*, Baïdy Sy Kane2, Yetna Tcheindah1, Kaba Condé3, Coumba Diouf1, Léra Géraud Akpo4, Ibrahima Faye4, Saïdou Diallo1

1Department of Rheumatology, University Hospital Aristide Le Dantec of Dakar, Senegal

2Department of Internal Medicine, University Hospital Aristide Le Dantec of Dakar, Senegal

3Department of Rheumatology, University Hospital Ignace Deen of Conakry, Guinea

4Department of Radiology, University Hospital Aristide Le Dantec of Dakar, Senegal

View / Download Pdf

Moustapha Niasse1*, Baïdy Sy Kane2, Abdou Majib Gaye3, El Hadji Modou Ndiaye2, Ibrahima Faye4, Maïmouna Sow2, Tafsir Ngary Ka2, Alioune Badara Diallo2, Atoumane Faye2, Saïdou Diallo1

1Department of Rheumatology, Aristide Le Dantec Teaching Hospital; Cheikh Anta DIOP University of Dakar, Senegal

2Department of Internal Medicine, Aristide Le Dantec Teaching Hospital; Cheikh Anta DIOP University of Dakar, Senegal

3Department of Anatomy and pathology, Aristide Le Dantec Teaching Hospital; Cheikh Anta DIOP University of Dakar, Senegal

4Department of Radiology, Aristide Le Dantec Teaching Hospital; Cheikh Anta DIOP University of Dakar, Senegal

DOI: 10.29245/2572-9411/2019/3.1185 View / Download Pdf

Ana Paula Vanz1, Têmis Maria Félix2,3, Neusa Sica da Rocha4, Ida Vanessa D. Schwartz2,5*

1Nurse department, Faculdades Integradas de Taquara, Taquara, Brazil

2Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil

3Postgraduate Program in Child and Adolescent Health, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

4Postgraduate Program in Medical Sciences: Psychiatry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

5Department of Genetics, Universidade Federal do Rio Grande do Sul, Brazil

DOI: 10.29245/2572-9411/2019/3.1175 View / Download Pdf

Alberto Migliore1*, Gianfranco Gigliucci1, Sandro Tormenta2, Angelo De Cata3, Luca Gallelli4, Giovanni Iolascon5

1Rheumatology Unit and Research Center, S. Pietro Fatebenefratelli Hospital, Rome, Italy

2Radiology Unit, S. Pietro Fatebenefratelli Hospital, Rome, Italy

3Department of Medical Sciences, Division of Internal Medicine and Rheumatology Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo (FG), Italy

4Chair of Pharmacology Department of Health Science, University of Catanzaro School of Medicine, and Operative Unit of Clinical Pharmacology and Pharmacovigilance, Azienda Ospedaliera MaterDomini, Catanzaro, Italy

5Department of Medical and Surgical Specialties and Dentistry, University of Campania "Luigi Vanvitelli", Naples, Italy

Hip osteoarthritis (OA) causes a set of symptoms that may lead to severe patient impairment, social isolation and morbidity, especially in the elderly. Eventually, patients become candidates for total hip replacement (THR); yet surgery may cause morbidity, increase costs and be too risky in some cases. Viscosupplementation (VS) by intra-articular hyaluronic acid (HA) injection has been shown to be effective to treat symptoms consequent to knee OA. VS is a viable option to treat hip OA too, provided that appropriate techniques are used to inject HA into the articular space. To this end, ultrasound-guided approaches have been developed that allow appropriate intra-articular injection eliminating the risk of exposure to ionizing radiation entailed by fluoroscopy. This review summarizes the results of clinical investigations concerning the use of a high molecular weight HA formulation, Hyalubrix/HyalOne, for treating hip OA symptoms. These results show that Hyalubrix/HyalOne has an enhanced safety profile, is effective from the first injection, significantly reduces NSAIDs consumption, and can be used for repeated therapy cycles over more years as a conservative therapy to delay THR. Nevertheless, it must be also considered that a significant placebo effect linked to intra-articular injections may exist, thus reducing the magnitude of HA benefits.

DOI: 10.29245/2572-9411/2019/2.1181 View / Download Pdf

Moustapha Niasse1*, Baïdy Sy Kane2, Kaba Condé3, Silly Touré4, Lamine Sarr5, Coumba Diouf1, Saïdou Diallo1

1Department of Rheumatology, University Hospital Aristide Le Dantec of Dakar, Senegal

2Department of Internal Medicine, University Hospital Aristide Le Dantec of Dakar, Senegal

3Department of Rheumatology, University Hospital Ignace Deen of Conakry, Guinea

4Department of Stomatology and Maxillofacial surgery, University Hospital Aristide Le Dantec of Dakar, Senegal

5Department of Orthopaedics and Traumatology, University Hospital Aristide Le Dantec of Dakar, Senegal

Multiple exostosis disease is one of the hereditary diseases with autosomal dominant transmission. It is characterized by the proliferation of bone protuberances, especially located in the metaphysis of long bones.

Since 1993, advances have been noted in knowledge of the pathophysiology of this disease, in particular with the discovery of the mutation of EXT genes, found in 80% of multiple exostosis disease. These genes, tumor suppressors, code for proteins involved in the synthesis of heparan sulfates. The deficiency in quantity and quality of heparan sulfates leads to changes in certain metabolic processes, which leads to the development of ectopic growth plaques. This is responsible for the development of exostosis, but also for the low longitudinal growth of long bones. The disease phenotype may also associate abnormalities in the shape and length of long bones, such as the typical “Bessel Hagen” deformity. Clinically, bone masses are often painless. The rare complication (2 to 5% of cases) but the most feared is the transformation into chondrosarcoma, which motivates regular clinical and radiological monitoring of these patients. Treatment, mainly surgical, is indicated in case of symptoms (pain, increased exostosis volume after the end of growth, compression of neighboring organs.

DOI: 10.29245/2572-9411/2019/2.1182 View / Download Pdf

Ali M Agha1, Jeremy Burt2*

1The McGovern Medical School at UT Houston, Department of Internal Medicine, USA

2AdventHealth Orlando, Department of Radiology, USA

DOI: 10.29245/2572-9411/2019/2.1180 View / Download Pdf

Dinesha M. Vidanapathirana1,2*, Eresha Jasinge1, Samantha Waidyanatha3, Amanda J. Hooper4,5, John R. Burnett4,5

1Department of Chemical Pathology, Lady Ridgeway Hospital for Children, Sri Lanka

2Department of Pathology, Faculty of Medical Sciences, University of Sri Jayewardenepura, Sri Lanka

3Department of Paediatrics, Lady Ridgeway Hospital, Sri Lanka

4Department of Clinical Biochemistry, PathWest Laboratory Medicine, Royal Perth Hospital and Fiona Stanley Hospital Network, Perth, Australia

5School of Medicine, University of Western Australia, Australia

Abetalipoproteinemia (ABL) is a rare autosomal recessive disorder of lipoprotein metabolism caused by mutations in the microsomal triglyceride transfer protein (MTTP) gene. To date, less than 100 cases of ABL have been reported worldwide. It is characterized biochemically by the absence or extremely low levels of low-density lipoproteins in the blood. We report a four-month-old girl, born to consanguineous parents, who presented with steatorrhea, failure to thrive, marked hypolipidemia and acanthocytosis, with a similar history having been noted in her older sibling. DNA sequencing revealed the infant to be homozygous for a novel pathogenic MTTP splice variant c.394-2A?C. Family screening revealed her sister to be homozygous for the same MTTP variant while her parents were heterozygotes. Early diagnosis and treatment of ABL in the form of a low-fat diet and fat-soluble vitamin supplementation can mitigate neuropathy and retinopathy. We believe that this is the first identification of an infant with a novel mutation for abetalipoproteinemia in Sri Lanka.

DOI: 10.29245/2572-9411/2019/2.1176 View / Download Pdf

Gang Wang*

Department of Pathology, BC Cancer Vancouver Centre, University of British Columbia, Vancouver, BC, Canada

Metastatic carcinomas to the testis are extremely rare and have been reported only in autopsy series or case reports. However, when they occur, the metastatic tumors in the testis are usually unilateral and solitary, may have overlap growth patterns and cytological features with primary testicular tumors, including those of rete/epididymis origin, mesothelial origin and Sertoli cell tumor. It will make the diagnosis very challenging, especially when there is no known history of a primary tumor in other sites. Metastatic prostatic adenocarcinoma counts nearly half of the overall metastatic carcinoma in the testis, followed by colorectal carcinoma and renal cell carcinoma. Here, we review our experience and summarize the reported cases from the literature, to emphasize some of the unusual aspects of metastatic carcinoma to the testis, and discuss the main differential diagnoses for this rare condition. Awareness of the features of these tumors, consideration of the possibility of metastasis and appropriate ancillary studies are the keys to the accurate diagnosis of these cases.

DOI: 10.29245/2572-9411/2019/2.1177 View / Download Pdf

Boris M. Ariel1,2*, Ivetta V. Dvorakovskaya1,3, Ludmila N. Novikova3, Mikhail M. Ilkovich3

1St. Petersburg Research Institute of Phthisiopulmonology, Health Ministry of Russia, St. Petersburg, Russia

2St. Petersburg City Mortem Bureau, St. Petersburg, Russia

3Pulmonology Clinic of Pavlov State Medical University, St. Petersburg, Russia

Pulmonary alveolar proteinosis (PAP) is a rare interstitial lung disease with severe impairment of respiratory function caused by some genetic abnormalities of surfactant production and utilization. One of the clue moments in the pathogenesis of this disease which can lead to respiratory failure and death is the pulmonary fibrosis development occurring occasionally in patients with moderate and severe PAP. According to our own experience in 1977-2018 whole and segmental lung lavage remains the first-line treatment of PAP; 70 patients (82%) had shown an improvement after this treatment. A noticeable improvement was achieved in 67 patients (79%), and no serious complications were observed. The 5-year survival rate reached 100%. Nevertheless, delayed diagnosis and incorrect administration of antibiotics and tuberculostatics reduce the probability of a long symptom-free period after lung lavage and resolution of the disease.

DOI: 10.29245/2572-9411/2019/2.1172 View / Download Pdf

Juan Luis Fernández-Martínez*, Oscar Álvarez, Enrique J. DeAndrés-Galiana, Javier Fernández-Sánchez de la Viña, Leticia Huergo

Group of Inverse Problems, Optimization and Machine Learning. Department of Mathematics. University of Oviedo, Oviedo, 33007, Asturias, Spain.

In this paper we present a robust methodology to deal with phenotype prediction problems associated to drug repositioning in rare diseases, which is based on the robust sampling of altered pathways. We show the application to the analysis of IBM (Inclusion Body Myositis) providing new insights about the mechanisms involved in its development: cytotoxic CD8 T cell-mediated immune response and pathogenic protein accumulation in myofibrils related to the proteasome inhibition. The originality of this methodology consists of performing a robust and deep sampling of the altered pathways and relating these results to possible compounds via the connectivity map paradigm. The methodology is particularly well-suited for the case of rare diseases where few genetic samples are at disposal. We believe that this method for drug optimization is more effective and complementary to the target centric approach that loses efficacy due to a poor understanding of the disease mechanisms to establish an optimum mechanism of action (MoA) in the designed drugs. However, the efficacy of the list of drugs and gene targets provided by this approach should be preclinically validated and clinically tested. This methodology can be easily adapted to other rare and non-rare diseases.

DOI: 10.29245/2572-9411/2019/2.1174 View / Download Pdf

Xia Chen1, Xue Xiao2, Fei Guo3*

1Department of Gynecology and Obstetrics, The First Affiliated Hospital of Nanchang University, Nanchang, China

2Anesthesiology of the Second Clinical Medical College, Nanchang University

3Burn Center, The First Affiliated Hospital of Nanchang University, Nanchang, China

Histone demethylation is an important part of epigenetic modifications, involving in multiple physiological and pathophysiological processes such as proliferation, differentiation, senescence, apoptosis, reprogramming and so on. JmjC domain-containing protein D3 (JMJD3, also called KDM6B) specifically demethylates lysine 27 on histone H3 (H3K27me3), a repressive epigenetic mark, therefore modulating the expression of target genes. JMJD3 can be strongly and quickly induced by various inflammatory stimuli and cellular stresses, and can enhance pro-inflammatory reactions as well as anti-inflammatory reactions by targeting diverse transcription factors in gene promoters and bodies. Additionally, JMJD3 has a dual effect on many types of cancers through binding to promoters of oncogenes or suppressor genes. As is known to us all, in the occurrence and development of various diseases including inflammation and cancer, JMJD3 plays a crucial role, which has triggered a research boom among numerous scholars over the years. In this review, we primarily focused on the roles of JMJD3 in inflammation and cancers, and briefly discussed its application prospect, laying a theoretical foundation for further research and providing a train of thought for the prevention and treatment of related diseases.

DOI: 10.29245/2572-9411/2019/1.1166 View / Download Pdf

Neslihan Y?ld?r?m Saral, Fehime Benli Aksungar*, Mustafa Serteser

Acibadem University, School of Medicine, Department of Biochemistry, Acibadem Labmed Clinical Laboratories, Department of Metabolism Istanbul, Turkey

Inherited metabolic diseases (IMDs), comprise a large class of genetic diseases affecting the metabolism. Expanded newborn screening from dried dried blood spot (DBS) samples for inborn errors of metabolism has increased the detection of metabolic disorders in asymptomatic newborns and reduced the morbidity and mortality by early interventions. Organic acidurias (OADs) arise from the defects in the intermediary metabolic pathways of carbohydrate, amino acid and fatty acid oxidation, leading to the accumulation of organic acids in tissues and their subsequent excretion in urine. Glutaric acidurias are a group of OADs which have three major types with different genetic mutations affecting different metabolic enzymes. In this mini-review we will compare three types of GA and their genotypes, symptoms, diagnosis, and treatments will be discussed briefly.

DOI: 10.29245/2572-9411/2019/1.1171 View / Download Pdf

Silvina Noemí Contreras-Capetillo1*, Melania Abreu-González2

1Laboratorio de Genética, Centro de Investigaciones Regionales Dr. Hideyo Noguchi, Mérida, Yucatán, México

2Laboratorio de Biología Molecular y Secuenciación Masiva. Genos Médica, Centro Especializado en Genética, Ciudad de México, México

In 2013, Bainbridge-Ropers syndrome (MIM #615485) was described in patients with severe global developmental delay, postnatal microcephaly and feeding problems due to heterozygous loss of function variants in the ASXL3 gene. The ASXL3 is part of the ASXL gene family involved in gene expression during embryogenesis and they participate as epigenetic scaffolds capable of interacting with complex modifiers of chromatin and diverse transcription factors. Germline variants in ASXL1, ASXL2 and ASXL3 have been associated with neurodevelopmental disorders which clinical phenotypic presentation resembles to Bainbridge-Ropers syndrome thus elucidating these types of overlapping genetic disorders is challenging. Up to now, approximately forty patients have been confirmed with this syndrome by next generation sequencing. The implementation of whole exome sequencing allows early identification and definitive diagnosis of patients with clinically unestablished phenotypes, as seen in AXL3 gene. This review discusses clinical and molecular features of variants in AXL3 gene associated with Bainbridge-Ropers syndrome.

DOI: 10.29245/2572-9411/2019/1.1160 View / Download Pdf

Rui-Ru Ji1*, Tatiana Serebriyskaya2,3, Natalia Kuzkina2,3

1Alexion Pharmaceuticals, Inc., 121 Seaport Boulevard, Boston, MA 02210, USA

2EPAM Systems, 22/2 Zastavskaya Street, MegaPark, 196084, Saint-Petersburg, Russia

3Moscow Institute of Physics and Technology, School of Biological and Medical Physics, 9 Institutskiy per., Dolgoprudny, 141701, Moscow, Russia

Genetic information provides important guidance for long-term management of patients with atypical hemolytic uremic syndrome (aHUS), an extremely rare disease that primarily affects a patient’s kidney. To better understand the phenotypic impact of variants identified in aHUS patients, we systematically mined the National Library of Medicine database for case studies of aHUS patients with identifiable genetic variants. Allelic variants from 10 genes (C3, CFB, CFH, CFI, CFHR1, CFHR3, CFHR5, DGKE, CD46/MCP, and THBD) associated with aHUS were collected from 1652 patients. We analyze the enrichment of genetic variants in this “literature cohort” compared with a reference population, the Genome Aggregation Database (gnomAD). We also used a number of tools to predict the pathogenicity of the variants, attempting to reconcile all the results using the protein structure and conservation data. In total, we identified 447 unique genetic variants: 301 of these were not present in the gnomAD database and thus have “moderate” evidence of pathogenicity; 33 variants have “strong” evidence of pathogenicity by enrichment analysis. This study showcases an in silico framework that patient data aggregation and a large scale sequencing database provided a novel opportunity to understand genotype-phenotype associations in aHUS. This framework can be efficiently applied to other rare diseases where data are sparse to help improve the diagnosis and management of these patients.

aHUS: atypical hemolytic uremic syndrome; gnomAD: Genome Aggregation Database; CD46/MCP: cluster of differentiation 46/membrane cofactor protein; CFH: complement factor H; CFI: complement factor I; CFB: complement factor B; C3: complement component 3; ACMG: American College of Medical Genetics; AF: allele frequency; CFHR1: complement factor H-related protein 1; CFHR3: complement factor H-related protein 3; CFHR5: complement factor H-related protein 5; DGKE: diacylglycerol kinase epsilon; THBD: thrombomodulin; MEDLINE: Medical Literature Analysis and Retrieval System Online; VEP: variant effect predictor; SIFT: sorts intolerant from tolerant substitutions; PROVEAN: protein variation effect analyzer; FATHMM: functional analysis through Hidden Markov Models

DOI: 10.29245/2572-9411/2018/1.1168 View / Download Pdf

Saika Amreen, Yaqoob Wani, Yawar Yaseen, Arshad Parray, Tariq A. Gojwari

Dept. Of Radiodiagnosis & Imaging, SKIMS, Soura, Srinagar, Jammu and Kashmir, India

A 38-year-old primigravida delivered a healthy baby via cesarean section. The patient complained of vague abdominal discomfort a few weeks after surgery. Though blood work was unremarkable, an ultrasound revealed a deep pelvic hypoechoic collection. Patient was afebrile and blood work was unremarkable for infectious etiology. Hemoglobin was normal. The patient was otherwise healthy. This was 6 years ago. The lesion still persists.

DOI: 10.29245/2572-9411/2018/1.1165 View / Download Pdf