A review of treatment modalities in gyrate atrophy of the choroid and retina (GACR)

Gyrate atrophy of the choroid and retina (GACR) is a rare inborn error of amino acid metabolism caused by bi-allelic variations in OAT. GACR is characterised by vision decline in early life eventually leading to complete blindness, and high plasma ornithine levels. There is no curative treatment for GACR, although several therapeutic modalities aim to slow progression of the disease by targeting different steps within the ornithine pathway. No international treatment protocol is available. We systematically collected all international literature on therapeutic interventions in GACR to provide an overview of published treatment effects. Methods: Following the PRISMA guidelines, we conducted a systematic review of the English literature until December 22nd 2020. PubMed and Embase databases were searched for studies related to therapeutic interventions in patients with GACR. Results: A total of 33 studies (n = 107 patients) met the inclusion criteria. Most studies were designed as case reports (n = 27) or case series (n = 4). No randomised controlled trials or large cohort studies were found. Treatments applied were protein-restricted diets, pyridoxine supplementation, creatine or creatine precursor supplementation, L-lysine supplementation, and proline supplementation. Protein-restricted diets lowered ornithine levels ranging from 16.0-91.2%. Pyridoxine responsiveness was reported in 30% of included mutations. Lysine supplementation decreased ornithine levels with 21-34%. Quality assessment showed low to moderate quality of the articles. Conclusions: Based primarily on case reports ornithine levels can be reduced by using a protein restricted diet, pyridoxine supplementation (variation-dependent) and/or lysine supplementation. The lack of pre-defined clinical outcome measures and structural follow-up in all included studies impeded conclusions on clinical effectiveness. Future research should be aimed at 1) Unravelling the OAT biochemical pathway to identify other possible pathologic metabolites besides ornithine, 2) Pre-defining GACR specific clinical outcome measures, and 3) Establishing an international historical cohort. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).Ophthalmic researc

Systematic Review of N-of-1 Studies in Rare Genetic Neurodevelopmental Disorders: The Power of 1

Contains fulltext : 232644.pdf (Publisher’s version ) (Open Access)OBJECTIVE: To improve the use of N-of-1 studies in rare genetic neurodevelopmental disorders, we systematically reviewed the literature and formulated recommendations for future studies. METHODS: The systematic review protocol was registered in the PROSPERO International Prospective Register of Systematic Reviews (CRD42020154720). EMBASE and MEDLINE were searched for relevant studies. Information was recorded on types of interventions, outcome measures, validity, strengths, and limitations using standard reporting guidelines and critical appraisal tools. Qualitative and descriptive analyses were performed. RESULTS: Twelve studies met the N-of-1 inclusion criteria, including both single trials and series. Interventions were mainly directed to neuropsychiatric manifestations. Main strengths were the use of personalized and clinically relevant outcomes in most studies. Generalizability was compromised due to limited use of validated and generalizable outcome measures. CONCLUSION: N-of-1 studies are sporadically reported in rare genetic neurodevelopmental disorders. Properly executed N-of-1 studies may provide a powerful alternative to larger randomized controlled trials in rare disorders and a much needed bridge between practice and science. We provide recommendations for future N-of-1 studies in rare genetic neurodevelopmental disorders, ultimately optimizing evidence-based and personalized care

Sialic acid catabolism by N-acetylneuraminate pyruvate lyase is essential for muscle function

Contains fulltext : 200388.pdf (publisher's version ) (Open Access

Successful Treatment of Hereditary Folate Malabsorption With Intramuscular Folinic Acid

Item does not contain fulltextBACKGROUND: Hereditary folate malabsorption is a multisystem disease owing to biallelic variants in the gene encoding the proton-coupled folate transporter. Hereditary folate malabsorption is treated with folinic acid, aimed to restore blood and cerebrospinal fluid folate levels. Little is known as to whether oral or intramuscular supplementation of folinic acid is most effective. METHODS: Here we describe a one-year-old boy with hereditary folate malabsorption presenting with the typical features including failure to thrive, aphthous stomatitis, macrocytic anemia along with severe developmental impairment and epilepsy, as well as a magnetic resonance imaging of the brain showing bilateral occipital, cortical calcifications characteristic of hereditary folate malabsorption. We compared the effect of treatment with oral folinic acid versus intramuscular folinic acid supplementation by measuring plasma and cerebrospinal fluid folate levels. RESULTS: Compared with oral administration, intramuscular treatment resulted in higher folate levels in blood and, most importantly, normalization of folate levels in cerebrospinal fluid. Clinically, nearly all systemic and neurological symptoms resolved. CONCLUSION: Normal cerebrospinal fluid folate levels can be achieved in individuals with hereditary folate malabsorption with intramuscular (but not with oral) administration of folinic acid.5 p

Clinical and biochemical footprints of inherited metabolic diseases. XII. Immunological defects.

Immunological problems are increasingly acknowledged manifestations in many inherited metabolic diseases (IMDs), ranging from exaggerated inflammation, autoimmunity and abnormal cell counts to recurrent microbial infections. A subgroup of IMDs, the congenital disorders of glycosylation (CDG), includes CDG types that are even classified as primary immunodeficiencies. Here, we reviewed the list of metabolic disorders reported to be associated with various immunological defects and identified 171 IMDs accompanied by immunological manifestations. Most IMDs are accompanied by immune dysfunctions of which immunodeficiency and infections, innate immune defects, and autoimmunity are the most common abnormalities reported in 144/171 (84%), 44/171 (26%) and 33/171 (19%) of IMDs with immune system involvement, respectively, followed by autoinflammation 17/171 (10%). This article belongs to a series aiming at creating and maintaining a comprehensive list of clinical and metabolic differential diagnoses according to organ system involvement