Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function

Next‐generation sequencing (NGS) has been instrumental in solving the genetic basis of rare inherited diseases, especially neurodevelopmental syndromes. However, functional workup is essential for precise phenotype definition and to understand the underlying disease mechanisms. Using whole exome (WES) and whole genome sequencing (WGS) in four independent families with hypotonia, neurodevelopmental delay, facial dysmorphism, loss of white matter, and thinning of the corpus callosum, we identified four previously unreported homozygous truncating PPP1R21 alleles: c.347delT p.(Ile116Lysfs*25), c.2170_2171insGGTA p.(Ile724Argfs*8), c.1607dupT p.(Leu536Phefs*7), c.2063delA p.(Lys688Serfs*26) and found that PPP1R21 was absent in fibroblasts of an affected individual, supporting the allele's loss of function effect. PPP1R21 function had not been studied except that a large scale affinity proteomics approach suggested an interaction with PIBF1 defective in Joubert syndrome. Our co‐immunoprecipitation studies did not confirm this but in contrast defined the localization of PPP1R21 to the early endosome. Consistent with the subcellular expression pattern and the clinical phenotype exhibiting features of storage diseases, we found patient fibroblasts exhibited a delay in clearance of transferrin‐488 while uptake was normal. In summary, we delineate a novel neurodevelopmental syndrome caused by biallelic PPP1R21 loss of function variants, and suggest a role of PPP1R21 within the endosomal sorting process or endosome maturation pathway

Hunter disease eClinic: interactive, computer-assisted, problem-based approach to independent learning about a rare genetic disease

<p>Abstract</p> <p>Background</p> <p>Computer-based teaching (CBT) is a well-known educational device, but it has never been applied systematically to the teaching of a complex, rare, genetic disease, such as Hunter disease (MPS II).</p> <p>Aim</p> <p>To develop interactive teaching software functioning as a virtual clinic for the management of MPS II.</p> <p>Implementation and Results</p> <p>The <it>Hunter disease eClinic</it>, a self-training, user-friendly educational software program, available at the Lysosomal Storage Research Group (<url>http://www.lysosomalstorageresearch.ca</url>), was developed using the Adobe Flash multimedia platform. It was designed to function both to provide a realistic, interactive virtual clinic and instantaneous access to supporting literature on Hunter disease. The <it>Hunter disease eClinic </it>consists of an <it>eBook </it>and an <it>eClinic</it>. The <it>eClinic </it>is the interactive virtual clinic component of the software. Within an environment resembling a real clinic, the trainee is instructed to perform a medical history, to examine the patient, and to order appropriate investigation. The program provides clinical data derived from the management of actual patients with Hunter disease. The <it>eBook </it>provides instantaneous, electronic access to a vast collection of reference information to provide detailed background clinical and basic science, including relevant biochemistry, physiology, and genetics. In the <it>eClinic</it>, the trainee is presented with quizzes designed to provide immediate feedback on both trainee effectiveness and efficiency. User feedback on the merits of the program was collected at several seminars and formal clinical rounds at several medical centres, primarily in Canada. In addition, online usage statistics were documented for a 2-year period. Feedback was consistently positive and confirmed the practical benefit of the program. The online English-language version is accessed daily by users from all over the world; a Japanese translation of the program is also available.</p> <p>Conclusions</p> <p>The Hunter disease <it>eClinic </it>employs a CBT model providing the trainee with realistic clinical problems, coupled with comprehensive basic and clinical reference information by instantaneous access to an electronic textbook, the <it>eBook</it>. The program was rated highly by attendees at national and international presentations. It provides a potential model for use as an educational approach to other rare genetic diseases.</p

Guidelines for acute management of hyperammonemia in the Middle East region

Majid Alfadhel,1,2 Fuad Al Mutairi,1,2 Nawal Makhseed,3 Fatma Al Jasmi,4 Khalid Al-Thihli,5 Emtithal Al-Jishi,6 Moeenaldeen AlSayed,7 Zuhair N Al-Hassnan,7,8 Fathiya Al-Murshedi,5 Johannes H&auml;berle,9 Tawfeg Ben-Omran10 Middle East Hyperammonemia and Urea Cycle Disorders Scientific Group (MHUSG) 1Department of Pediatrics, Division of Genetics, 2King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Saudi Arabia; 3Department of Pediatrics, Jahra Hospital, Ministry of Health, Jahra City, Kuwait; 4Department of Pediatric, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates; 5Genetic and Developmental Medicine Clinic, Sultan Qaboos University Hospital, Muscat, Sultanate of Oman; 6Salmaniya Medical Complex, Arabian Gulf University, Manama, Bahrain; 7Department of Medical Genetics, King Faisal Specialist Hospital &amp; Research Center, 8The National Newborn Screening Program, Ministry of Health, Riyadh, Saudi Arabia; 9Department of Pediatrics, Division of Metabolism and Children&rsquo;s Research Center, University Children&rsquo;s Hospital Zurich, Zurich, Switzerland; 10Division of Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar Background: Hyperammonemia is a life-threatening event that can occur at any age. If treated, the early symptoms in all age groups could be reversible. If untreated, hyperammonemia could be toxic and cause irreversible brain damage to the developing brain.Objective: There are major challenges that worsen the outcome of hyperammonemic individuals in the Middle East. These include: lack of awareness among emergency department physicians about proper management of hyperammonemia, strained communication between physicians at primary, secondary, and tertiary hospitals, and shortage of the medications used in the acute management of hyperammonemia. Therefore, the urge to develop regional guidelines is extremely obvious.Method: We searched PubMed and Embase databases to include published materials from 2011 to 2014 that were not covered by the European guidelines, which was published in 2012. We followed the process of a Delphi conference and involved one preliminary meeting and two follow-up meetings with email exchanges between the Middle East Hyperammonemia and Urea Cycle Disorders Scientific Group regarding each draft of the manuscript.Results and discussion: We have developed consensus guidelines based on the highest available level of evidence. The aim of these guidelines is to homogenize and harmonize the treatment protocols used for patients with acute hyperammonemia, and to provide a resource to not only metabolic physicians, but also physicians who may come in contact with individuals with acute hyperammonemia.Conclusion: These suggested guidelines aim to ease the challenges faced by physicians dealing with acute hyperammonemia in the region. In addition, guidelines have demonstrated useful collaboration between experts in the region, and provides information that will hopefully improve the outcomes of patients with acute hyperammonemia. Keywords: hyperammonemia, inborn errors of metabolism, urea cycle, acute management, ammonia, Middle Eas

Clinical, morphological, biochemical, imaging and outcome parameters in 21 individuals with mitochondrial maintenance defect related to FBXL4 mutations

Contains fulltext : 154784.pdf (publisher's version ) (Closed access)FBXL4 deficiency is a recently described disorder of mitochondrial maintenance associated with a loss of mitochondrial DNA in cells. To date, the genetic diagnosis of FBXL4 deficiency has been established in 28 individuals. This paper retrospectively reviews proxy-reported clinical and biochemical findings and evaluates brain imaging, morphological and genetic data in 21 of those patients. Neonatal/early-onset severe lactic acidosis, muscular hypotonia, feeding problems and failure to thrive is the characteristic pattern at first presentation. Facial dysmorphic features are present in 67 % of cases. Seven children died (mean age 37 months); 11 children were alive (mean age at follow-up 46 months), three children were lost to follow-up. All survivors developed severe psychomotor retardation. Brain imaging was non-specific in neonates but a later-onset, rapidly progressive brain atrophy was noted. Elevated blood lactate and metabolic acidosis were observed in all individuals; creatine kinase was elevated in 45 % of measurements. Diagnostic workup in patient tissues and cells revealed a severe combined respiratory chain defect with a general decrease of enzymes associated with mitochondrial energy metabolism and a relative depletion of mitochondrial DNA content. Mutations were detected throughout the FBXL4 gene albeit with no clear delineation of a genotype-phenotype correlation. Treatment with "mitochondrial medications" did not prove effective. In conclusion, a clinical pattern of early-onset encephalopathy, persistent lactic acidosis, profound muscular hypotonia and typical facial dysmorphism should prompt initiation of molecular genetic analysis of FBXL4. Establishment of the diagnosis permits genetic counselling, prevents patients undergoing unhelpful diagnostic procedures and allows for accurate prognosis